TWI496780B - Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators - Google Patents

Description

Novel substituted bicyclic heterocyclic compounds as modulators of gama secretase

The present invention relates to the use of novel substituted bicyclic heterocyclic compounds as modulators of gama secretion. The invention further relates to a process for the preparation of the novel compound, a pharmaceutical composition comprising the compound as an active ingredient, and the use of the compound as a medicament.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes loss of memory, cognition, and behavioral stability. AD affects 6-10% of people over 65 years old and up to 50% over 85 years old. It is the cause of dementia and is the third cause of death after cardiovascular disease and cancer. Today, it is not effective in treating AD, and the total annual loss associated with AD in the United States exceeds 100 billion.

There are no simple causes of AD. However, the associated risk factors include (1) age, (2) family history, and (3) head injury; other factors, including environmental toxins and low levels of education. Intracerebral marginal and cortical specific neuropathy includes intracellular entanglement (neurofibrillary) consisting of extracellular deposition (amyloid plaques) of hyperphosphorylated tau and amyloid beta peptides (fibrillar aggregate) Tangle). The main components of amyloid plaques are amyloid β (A-β, Aβ or Aβ) peptides of various lengths. A variant thereof, Aβ1-42-peptide (Aβ-42) is believed to be the main triggering substance for amyloid formation. Another variant is the Aβ1-40-peptide (Aβ-40). Amyloid beta is a hydrolyzed protein product of a precursor protein (beta amyloid precursor protein (beta-APP or APP)).

The familial, early-onset AD chromosomal dominant pattern has been linked to the β-amyloid precursor protein (β-APP or APP) and the missense variation of presenilin proteins 1 and 2. In some patients, late-onset AD has been associated with a specific dual gene of the pro-lipoprotein E (ApoE) gene, and recently, in the discovery of α2-macroglobulin variants, it can be associated with at least 30% of the AD population. Despite this heterogeneity, all forms of AD present similar pathological findings. Genetic analysis has provided the best clue to a rational treatment for AD, and all the mutations found to date have influenced the production of the quality or quantity of amyloid peptides, such as Aβ-peptide (Aβ), especially Aβ42, and The "starch cascade hypothesis" of AD is strongly supported (Tanzi and Bertram, 2005, Cell 120, 545). The possible association between Aβ peptide production and AD pathology highlights the need for a better understanding of the mechanism of Aβ production and a strong and potent approach to the treatment of Aβ concentrations.

The release of Aβ peptide is regulated by at least two proteolytic activities called β- and γ-secretase cleavage, each located at the N-terminus (Met-Asp junction) and C-terminus of the Aβ peptide (residue 37 -42). On the secretory pathway, there is evidence that beta-secretase cleaves first, resulting in the secretion of s-APPβ (sβ) and retention of the 11 kDa membrane-bound carboxy-terminal fragment (CTF). The latter is believed to cause subsequent cleavage of the A[beta] peptide by gamma-secretase. In patients with certain variations in specific proteins (presenilin), the amount of longer isoform A[beta]42 is selectively increased and these variations have been correlated with early onset familial Alzheimer's disease. Therefore, Aβ42 is believed by many researchers to be the main cause of the onset of Alzheimer's disease.

It is now clear that gamma-secretase activity cannot be attributed to a single protein and is in fact associated with a collection of different proteins.

Gamma (gamma)-secretase activity is present in a multi-protein complex comprising at least four components: presenilin (PS) heterodimer, Nicastrin, aph-1 and pen-2. The amino- and carboxy-terminal PS fragments produced by endoproteolysis of the precursor protein constitute a PS heterodimer, and the aspartic acid at the two catalytic sites is located at the interface of the heterodimer. Nicastrin has recently been proposed as a Gamma-secretase-matrix receptor, and the functions of other Gamma-secretase members are not known, but they are all required for activity (Steiner, 2004. Curr. Alzheimer Research 1 (3) :175-181).

Thus, although the molecular mechanism of the second cleavage step is still difficult to understand to date, gamma-secretase-complexes have become a basic goal in the search for compounds for the treatment of Alzheimer's disease.

Various strategies have been proposed for the labeling of Alzheimer's gamma-secretase, by direct catalyzed positional characterization, development of matrix-specific inhibitors and modulators of gama-secretase activity (Marjaux et al., 2004. Drug Discovery Today: Therapeutic Strategies, Volume 1, 1-6). Therefore, various compounds have been described with a secretase as a target (Larner, 2004. Secretases as therapeutics targets in Alzheimer's disease: patents 2000-2004. Expert Opin. Ther. Patents 14, 1403-1420).

Indeed, this finding has recently been supported by biochemical studies showing the effects of certain NSAIDs on gamma-secretase (Weggen et al (2001) Nature 414, 6860, 212 and WO 01/78721 and US 2002/0128319; Morihara et Al (2002) J. Neurochem. 83, 1009; Eriksen (2003) J. Clin. Invest. 112, 440). The potential limitation of NSAIDs for the prevention or treatment of AD is its COX enzyme inhibitory activity, which can lead to deleterious side effects and its low CNS penetration (Peretto et al., 2005, J. Med. Chem. 48, 5705). -5720).

WO-2008/137139 relates to heterocyclic derivatives and their use as modulators of gama secretion.

WO-2005/115990 discloses cinnamide compounds for the treatment of neurodegenerative diseases caused by amyloid beta proteins, such as Alzheimer's disease, senile dementia, Down's syndrome and amyloidosis.

WO-2004/110350 relates to aryl compounds and their use in the regulation of amyloid beta.

WO-2007/131991 discloses imidazole as a MAPKAPK5 inhibitor a compound for the treatment of degenerative and inflammatory diseases.

WO-2004/017963 relates to benzimidazole as a factor Xa inhibitor for the treatment of thromboembolism.

There is a strong need for novel compounds that modulate gamma-secretase activity, thus opening the way for the treatment of Alzheimer's disease. It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art or to provide a useful alternative. Accordingly, it is an object of the present invention to provide such novel compounds.

Summary of the invention

The compounds of the invention have been found to be useful as modulators of gamases. The compounds of the invention and their pharmaceutically acceptable compositions are useful for the treatment or prevention of Alzheimer's disease.

The present invention relates to novel compounds of formula (I):

And a stereoisomeric form thereof, wherein Het ¹ is a 5- or 6-membered aromatic heterocyclic ring having the formula (a-1), (a-2), (a-3), (a-4) or (a- 5):

R ⁰ is H or C _1-4 alkyl; R ¹ is H, C _1-4 alkyl or C _1-4 alkoxy C _1-4 alkyl; R ² is C _1-4 alkyl; X is O or S; G ¹ is CH or N; G ² is CH, N or C substituted by C _1-4 alkyl; only G ¹ and G ² are not N at the same time; G ³ is CH or N; R ^10a And R ^{10b are} each independently hydrogen or C _1-4 alkyl; A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ² , A ³ and A ^{4 are} each independently CH, CF or N; only A ¹ , A ² , A ³ and A ^{4 are at} most N; Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-1) or (b-2): Z ¹ is CH or N; Z ² is CR ^4a or N; Z ³ is CH or N; only Z ¹ , Z ² and Z ^{3 are at} most one N; Y ¹ is CH or N; Y ² is CR ^4b or N; Y ³ is CH or N; wherein at most one of Y ¹ , Y ² and Y ³ is N; R ^4a is H; halogen; C _1-4 alkoxy; cyano; ring C _3-7 alkyl; a C _1-4 alkylcarbonyl group; a C _1-4 alkoxycarbonyl group; or a C _1-4 alkyl group, which is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and an amine group; R ^4b is H; halogen; C _1-4 alkoxy; cyano; cyclo C _3-7 alkyl; or C _1-4 alkyl, optionally optionally selected from halo and amine groups via one or more Substituted by a group of substituents; R ⁵ is H; halogen; cyano; C _1-4 alkoxy; C _2-6 alkenyl; or C _1-6 alkyl, optionally via one or more Substituted independently by a substituent selected from the group consisting of C _1-4 alkoxy and halogen; R ^6a is C _2-6 alkyl substituted with one or more halogen substituents; C _1-6 alkyl, Optionally consisting of one or more of each independently selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropyranyl, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkyl Substituent substituents; ring C _3-7 alkyl; C _{1- 4} -alkylcarbonyl; tetrahydropyranyl; Ar; R ⁸ R ⁹ N-carbonyl; or CH ₂ -O-Ar; R ^6b is C _2-6 alkyl substituted with one or more halogen substituents; _{a 1-6} alkyl group optionally arbitrarily selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropyranyl, cyclo C _3-7 alkoxy, and ring C _{3 -7} group consisting of alkyl substituents; C _3-7 cycloalkyl group; a phenyl group substituted with one or more substituents of the group C _3-7 cycloalkyl group, the phenyl group optionally substituted with one or more Substituted by a halogen substituent; piperidinyl; morpholinyl; pyrrolidinyl; NR ⁸ R ⁹ ; tetrahydropyranyl; O-Ar; C _1-6 alkoxy; C _1-6 alkylthio; ; CH ₂ —O—Ar; S—Ar; NCH ₃ —Ar; or NH—Ar; wherein each piperidinyl, morpholinyl, and pyrrolidinyl group may be optionally independently selected from C ₁ through one or more Substituted with a substituent group consisting of _-4 alkyl, C _2-6 alkenyl, C _1-4 alkylcarbonyl, halogen, and C _1-4 alkoxycarbonyl; wherein each Ar is independently phenyl, Optionally substituted by one or more of each independently selected from the group consisting of halogen, C _1-4 alkoxy, cyano, NR ⁸ R ⁹ , morpholinyl, C _1-4 alkyl, and substituted with one or more halogen substituents C _a substituent substituted with a group consisting of _1-4 alkyl groups; a pyridyl group optionally exemplified by one or more of each independently selected from the group consisting of halogen, C _1-4 alkoxy, cyano, C _1-4 alkyl, and Substituted by a substituent group consisting of one or more halogen substituent-substituted C _1-4 alkyl groups; An azolyl group optionally substituted with one or more C _1-4 alkyl substituents; or a thienyl group optionally substituted with one or more halogen substituents; each R ^{8 is} independently H or C _1-4 An alkyl group; each R ^{9 is} independently H or C _1-4 alkyl; R ⁷ is H, C _1-6 alkyl optionally substituted one or more of each independently selected from the group consisting of halogen, phenyl, and C _{1 a} substituent substituted by a group consisting of _-4 alkoxy groups; and pharmaceutically acceptable addition salts thereof, and solvates thereof.

The invention also relates to a process for the preparation of a compound of formula (I) and a pharmaceutical composition therewith.

This compound has surprisingly been found to regulate γ-secretase activity in vitro and in vivo, and thus can be used to treat or prevent Alzheimer's disease (AD), traumatic brain injury, mild cognitive impairment (MCI), aging, Dementia, Lewy bodies dementia, cerebral amyloid angiopathy, multiple infarct dementia, Down's syndrome, Parkinson's disease-related dementia, and β-amyloid-related dementia, preferably Alzheimer's disease and other symptoms of beta-amyloidosis (eg glaucoma).

In view of the pharmacology of the above compound of the formula (I), it is suitable for use as a medicament.

More particularly, the compounds are suitable for the treatment or prevention of Alzheimer's disease, cerebral amyloid angiopathy, multiple infarct dementia, boxer dementia or Down's syndrome.

The invention also relates to the use of a compound of formula (I), a stereoisomeric form thereof, and pharmaceutically acceptable acid or base addition salts and solvates thereof for the manufacture of a medicament for modulating gamma-secretase activity.

Preferably, modulation of gamma-secretase activity using a compound of formula (I) results in a decrease in the relative amount of A[beta]42-peptide production.

An advantage of a compound of the invention or a portion of a compound can be exhibited by its enhanced CNS-osmotic force.

The invention will now be further described, and in the following sections, different aspects of the invention will be defined in more detail. Except as expressly indicated to the contrary, the various aspects defined herein may be combined with any other point of view. In particular, any of the preferred or advantageous features indicated may be combined with any other preferred or advantageous features indicated.

Detailed description of the invention

When the compounds of the invention are recited, the terms used are understood to conform to the following definitions, unless otherwise specified in the context.

When indicating the number of substituents, the term "one or more" means one substituent to the highest number of substitutions possible, ie one hydrogen to all hydrogens are substituted by a substituent, each substituent being individually selected from the indicated groups. The group, but not exceeding the normal valence, and the substitution results in a chemically stable compound, i.e., the compound is sufficiently stable to be separated from the residue in the reaction mixture to a useful purity and formulated into a therapeutic agent. Accordingly, one, two, three or four substituents are preferred, especially one, two or three substituents are preferred, and more particularly, one substituent is preferred.

The term "halo" or "halogen" as part of a group or group is generally fluoro, chloro, bromo, iodo unless otherwise indicated.

The term as part of a group or a group of the "C _1-6 alkyl" represented by the formula C _n H _{2n +} hydrocarbon residues of _1, wherein n is a number of from 1 to 6. The C _1-6 alkyl group contains 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, more specifically 1 to 3 carbon atoms, more specifically 1 to 2 carbon atoms. An alkyl group can be straight or branched and can be substituted as indicated herein. When a subscript symbol is used herein after a carbon atom, the subscript symbol indicates that the group referred to may include the number of carbon atoms. Thus, for example, a C _1-6 alkyl group includes all straight-chain or branched alkyl groups having 1 to 6 carbon atoms, and thus includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-methyl-B. Base, butyl and its isomers (such as n-butyl, isobutyl and tert-butyl), pentyl and its isomers, hexyl and isomers thereof and the like.

The term "C _2-6 alkyl" as a part of a group or a group means a C _n H _2n+1 hydrocarbon residue of the formula wherein it is a number from 2 to 6. C _2-6 alkyl group contains 2 to 6 carbon atoms, especially 2 to 4 carbon atoms, more specifically 2 to 3 carbon atoms, and the alkyl group may be straight or branched, and may be as referred to herein Was replaced. When a subscript symbol is used herein after a carbon atom, the subscript symbol indicates that the group referred to may include the number of carbon atoms. Thus, for example, C _2-6 alkyl includes all straight-chain or branched alkyl groups having 2 to 6 carbon atoms, and thus includes, for example, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, butyl And its isomers (such as n-butyl, isobutyl and tert-butyl), pentyl and its isomers, hexyl and its isomers, and the like.

The term "C _1-4 alkyl" as a moiety or a moiety of a group denotes a hydrocarbon residue of the formula C _n H _2n+1 wherein n is a number from 1 to 4. The C _1-4 alkyl group contains 1 to 4 carbon atoms, particularly 1 to 3 carbon atoms, more specifically 1 to 2 carbon atoms. An alkyl group can be straight or branched and can be substituted as indicated herein. When a subscript symbol is used herein after a carbon atom, the subscript symbol indicates that the group referred to may include the number of carbon atoms. Thus, for example, C _1-4 alkyl includes all straight-chain or branched alkyl groups having from 1 to 4 carbon atoms, and thus includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-methyl-B. Base, butyl and its isomers (such as n-butyl, isobutyl and tert-butyl) and the like.

As part of a group or a group of "C _1-6 alkoxy" refers to devices having a group of the formula OR ^b, wherein R ^b is C _1-6 alkyl. Non-limiting examples of suitable C _1-6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, third Oxyl, pentyloxy and hexyloxy.

The term "C _1-4 alkoxy" as a moiety or a moiety of a group denotes a radical of the formula OR ^c wherein R ^c is C _1-4 alkyl. Non-limiting examples of suitable C _1-4 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy and third Oxygen.

In the framework of this application, a C _2-6 alkenyl group is a straight or branched hydrocarbon residue having from 2 to 6 carbon atoms containing a double bond, such as a vinyl group, a propenyl group, a butenyl group, Pentenyl, 1-propen-2-yl, hexenyl and the like.

The term "cyclo C _3-7 alkyl", alone or in combination, means a cyclic saturated hydrocarbon residue having from 3 to 7 carbon atoms. Non-limiting examples of suitable cyclic C _3-7 alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "cyclo C _3-7 alkoxy", alone or in combination, signifies a residue of the formula OR ^d wherein R ^d is cyclo C _3-7 alkyl. Non-limiting examples of suitable cyclic C _3-7 alkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.

The chemical name of the compound of the present invention is produced according to the nomenclature agreed by Chemical Abstracts Service.

In the case of tautomeric forms, it is apparent that other tautomeric forms not described are also included in the scope of the invention.

When any variation occurs in any composition more than once, the definitions are independent.

It will be appreciated that some of the compounds of formula (I), and their pharmaceutically acceptable addition salts and stereoisomeric forms, may contain one or more pairs of palm centers and exist in stereoisomeric forms.

The term "stereoisomeric" as used hereinabove is defined as all possible isomeric forms which the compounds of formula (I) may have. Unless otherwise stated or indicated, the chemical name of a compound means a mixture of all possible stereochemically isomeric forms, more particularly, the stereocenter may have an R- or S-configuration; in a divalent cyclic (partially) saturation The substituents on the residue may have a cis or trans configuration. A compound containing a double bond may have an E or Z-stereochemistry on the double bond. Stereoisomeric forms of the compounds of formula (I) are included within the scope of the invention.

When a particular stereoisomeric version is indicated, this means that the pattern is substantially separate, i.e., less than 50%, preferably less than 20%, more preferably less than 10%, and even more preferably less than 5%. More preferably less than 2% and optimally less than 1% of other isomers.

When a particular region of the regioisomeric form is indicated, this means that the pattern is substantially separate, i.e., less than 50%, preferably less than 20%, more preferably less than 10%, more preferably more preferably Less than 5%, more preferably less than 2% and optimally less than 1% of other isomers.

For therapeutic use, the salt of the compound of formula (I) is one in which the relative ion is pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be employed, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or unacceptable, are included within the scope of the invention.

The pharmaceutically acceptable acid and base addition salts described herein are intended to comprise the therapeutically active non-toxic acid and base addition salt forms which form the compound of formula (I). Pharmaceutically acceptable acid addition salts are conveniently obtained by treating the base form with a suitable acid comprising, for example, a mineral acid such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid Or an acid; or an organic acid such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (ie, oxalic acid), malonic acid, succinic acid (ie, succinic acid), maleic acid, fumaric acid, Acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminesulfonic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Conversely, the salt form can be converted to the free base form via treatment with a suitable base.

The compound of formula (I) containing an acidic proton may also be converted to its non-toxic metal or amine addition salt form by treatment with a suitable organic and inorganic base. Suitable basic salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts and the like, salts having an organic base such as primary, secondary and tertiary aliphatics. And aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, tetrabutylamine isomer, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, Di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, Pyridine, pyridine, quinoline and isoquinoline; benzathine, N -methyl-D-reducing glucosamine, hydrabamine salts, and salts with amino acids such as arginine , from the amine acid and so on. Conversely, the salt form can be converted to the free acid form by acid treatment.

The term solvate comprises hydrates and solvent addition forms which the compounds of formula (I) are able to form and salts thereof. Examples of such forms are, for example, hydrates, alcoholates and the like.

The compound of formula (I) prepared as described below can be synthesized as a racemic mixture of enantiomers which can be separated from one another by analytical procedures known in the art. The method of isolating the enantiomeric form of the compound of formula (I) comprises the use of liquid chromatography for the palm stationary phase. Whereas the reaction is stereospecific, the pure stereochemically isomeric form can also be obtained from the corresponding pure stereochemically isomeric forms of the appropriate starting materials. Preferably, if a particular stereoisomer is desired, the compound can be synthesized via stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

In the framework of the present application, the compounds of the present invention are intended to include all isotopic combinations of their chemical elements. In the framework of the present application, particularly when referring to a compound of formula (I), the chemical element comprises all isotopes and isotopic mixtures of such elements. For example, when referring to hydrogen, it is understood that ¹ H, ² H, ³ H and mixtures thereof are indicated.

Thus, the compounds of the present invention originally comprise a compound having one or more isotopes of one or more elements and mixtures thereof, including radioactive compounds, also known as radiolabeled compounds, wherein one or more non-radioactive atoms are radioisotopes thereof. Replacement. The term "radiolabeled compound" means any compound of formula (I), or a pharmaceutically acceptable salt thereof, which comprises at least one radioactive atom. For example, a compound can be labeled as a positron or a radioisotope emitted by a gamma. With regard to the radioligand-binding technique, the ³ H-atom or ¹²⁵ I-atom is the selected atom to be replaced. For imaging, the most commonly used positron-emitting (PET) radioisotopes are ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N, all produced by accelerators, with half-life of 20, 100, 2, and 10 minutes each. Since the half-life of these radioisotopes is so short, they are only used reasonably in the field with the accelerators used to make them, thus limiting their use. The most commonly used are ¹⁸ F, ^99m Tc, ²⁰¹ Tl and ¹²³ I. The operation of these radioisotopes, their manufacture, isolation, and incorporation into molecules are known to those skilled in the art.

In particular, the radioactive atomic system is selected from the group consisting of hydrogen, carbon, nitrogen, sulfur, oxygen, and halogen. In particular, the radioisotope is selected from the group consisting of ³ H, ¹¹ C, ¹⁸ F, ¹²² I, ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br.

As used in the specification and the appended claims, the <RTI ID=0.0> </ RTI> </ RTI> <RTIgt; By way of example, "a compound" means a compound or more than one compound.

The terms used in the above and other descriptions are understood by those skilled in the art.

Preferred features of the compounds of the invention are set forth below.

The present invention relates to novel compounds of formula (I):

And a stereoisomeric form thereof, wherein Het ¹ is a 5- or 6-membered aromatic heterocyclic ring having the formula (a-1), (a-2), (a-3), (a-4) or (a- 5):

R ⁰ is H or C _1-4 alkyl; R ¹ is H, C _1-4 alkyl or C _1-4 alkoxy C _1-4 alkyl; R ² is C _1-4 alkyl; X is O or S; G ¹ is CH or N; G ² is CH, N or C substituted by C _1-4 alkyl; only G ¹ and G ² are not N at the same time; G ³ is CH or N; R ^10a And R ^{10b are} each independently hydrogen or C _1-4 alkyl; A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ² , A ³ and A ^{4 are} each independently CH, CF or N; but at most two of A ¹ , A ² , A ³ and A ⁴ are N; Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-1) or (b-2):

Z ¹ is CH or N; Z ² is CR ^4a or N; Z ³ is CH or N; but at most one of Z ¹ , Z ² and Z ³ is N; Y ¹ is CH or N; Y ² is CR ^4b or N Y ³ is CH or N; but at most one of Y ¹ , Y ² and Y ³ is N; R ^4a is H; halogen; C _1-4 alkoxy; cyano; ring C _3-7 alkyl; C _{1 a 4} -alkylcarbonyl group; a C _1-4 alkoxycarbonyl group; or a C _1-4 alkyl group optionally substituted by one or more substituents each independently selected from the group consisting of a halogen and an amine group; R ^4b is H; halogen; C _1-4 alkoxy; cyano; C _3-7 cycloalkyl group; or C _1-4 alkyl, which is optionally substituted with one or more halogen, and each independently selected from the group consisting of consisting of Substituted by a group; R ⁵ is H; halogen; cyano; C _1-4 alkoxy; C _2-6 alkenyl; or C _1-6 alkyl, optionally independently of one or more Substituting a substituent of a group consisting of a C _1-4 alkoxy group and a halogen; R ^6a is a C _2-6 alkyl group substituted by one or more halogen substituents; a C _1-6 alkyl group, optionally By one or more groups independently selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropiperidyl, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkyl the substituents; C _3-7 cycloalkyl Group; C _1-4 alkylcarbonyl; tetrahydropyranyl group; Ar; R ⁸ R ⁹ N- carbonyl group; or CH ₂ -O-Ar; R ^6b is substituted with one or more halo substituents of C _{2- 6} alkyl; C _1-6 alkyl optionally substituted by one or more of each selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropyranyl, cyclo C _3-7 alkoxy group, a C _3-7 cycloalkyl group, and the group consisting of substituents; C _3-7 cycloalkyl group; a phenyl group substituted with one or more substituents of the group C _3-7 cycloalkyl group, the phenyl optionally Substituted with one or more halogen substituents; piperidinyl; morpholinyl; pyrrolidinyl; NR ⁸ R ⁹ ; tetrahydropyranyl; O-Ar; C _1-6 alkoxy; C _1-6 Alkylthio; Ar; CH ₂ -O-Ar; S-Ar; NCH ₃ -Ar; or NH-Ar; wherein each piperidinyl, morpholinyl, and pyrrolidinyl group may optionally be subjected to one or more Each of which is independently selected from the group consisting of a C _1-4 alkyl group, a C _2-6 alkenyl group, a C _1-4 alkylcarbonyl group, a halogen, and a C _1-4 alkoxycarbonyl group; wherein each Ar is independently Is a phenyl group which is optionally independently selected from halo, C _1-4 alkoxy, cyano, NR ⁸ R ⁹ , morpholinyl, C _1-4 alkyl, and one or more Multiple Su substituents consisting of C _1-4 alkyl groups of the substituents; pyridinyl which is optionally substituted with one or more each independently selected from the group consisting of halogen, C _1-4 alkoxy, cyano, C ₄ alkyl, halo, and substituted with one or more substituents consisting of C _1-4 alkyl group substituted with the substituent group; An azolyl group optionally substituted with one or more C _1-4 alkyl substituents; or a thienyl group optionally substituted with one or more halogen substituents; each R ^{8 is} independently H or C _1-4 An alkyl group; each R ^{9 is} independently H or C _1-4 alkyl; R ⁷ is H, optionally one or more groups independently selected from the group consisting of halogen, phenyl, and C _1-4 alkoxy a C _1-6 alkyl group substituted with a substituent; and a pharmaceutically acceptable addition salt thereof, and a solvate.

In a specific embodiment, the invention relates to a compound of formula (I) and stereoisomeric forms thereof, or any subgroup thereof as described in any other embodiment, wherein one or more, preferably All of the following restrictions:

(a) A ^2, A ³ A ⁴ each is independently CH or N; provided that A ^1, A ^2, A ³ and A ⁴ both up is N;

(b) Z ² is CR ^4a ;

(c) R ^4a is H; halogen; cyano; ring C _3-7 alkyl; C _1-4 alkylcarbonyl; C _1-4 alkoxycarbonyl; or C _1-4 alkyl, optionally One or more substituents each independently selected from the group consisting of halogen and an amine group;

(d) R ⁵ is H; halogen; C _1-4 alkoxy; C _2-6 alkenyl; or C _1-6 alkyl optionally substituted by one or more C _1-4 alkoxy substituents ;

(e) R ^6a is C _1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of Ar, C _1-6 alkoxy, and tetrahydropyranyl; Ring C _3-7 alkyl; C _1-4 alkylcarbonyl; tetrahydropyranyl; Ar; or R ⁸ R ⁹ N-carbonyl;

(f) R ^6b is a C _2-6 alkyl group substituted by one or more halogen substituents; a C _1-6 alkyl group optionally arbitrarily selected from Ar, C _1-6 alkoxy Substituted by a substituent consisting of a group consisting of a tetrahydropyranyl group and a cyclic C _3-7 alkyl group; a ring C _3-7 alkyl group; a ring C _3-7 alkyl group substituted with a phenyl substituent, The phenyl substituent is optionally substituted by one or more halogen substituents; unsubstituted pyrrolidinyl; NR ⁸ R ⁹ ; tetrahydropyranyl; A _r ; or CH ₂ -O-Ar;

(g) each Ar is independently phenyl optionally substituted by one or more of each independently selected from halo, C _1-4 alkoxy, C _1-4 alkyl, and substituted by one or more halogen substituents Substituted by a substituent group consisting of C _1-4 alkyl groups; An azolyl group optionally substituted with one or more C _1-4 alkyl substituents; or a thienyl group optionally substituted with one or more halogen substituents;

(h) each R ^{8 is} independently C _1-4 alkyl;

(i) each R ^{9 is} independently C _1-4 alkyl;

(j) R ⁷ is C _1-6 alkyl optionally substituted by one or more C _1-4 alkoxy substituents;

And pharmaceutically acceptable addition salts thereof, and solvates.

In a specific embodiment, the invention relates to a compound of formula (I) and stereoisomeric forms thereof, or any subgroup thereof as described in any other embodiment, wherein one or more, preferably All of the following restrictions:

(a) R ⁰ is H or methyl;

(b) R ¹ is H, methyl, isopropyl or methoxymethyl;

(c) R ² is a methyl group;

(d) G ² is CH, N or C substituted by methyl; only G ¹ and G ² are not N at the same time;

(e) R ^10a and R ^{10b are} each independently hydrogen or methyl;

(f) A ¹ is CR ³ or N; wherein R ³ is H, F or methoxy;

(g) A ² is CH or N;

(h) A ³ is CH;

(i) A ⁴ is CH or N;

(j) Z ² is CR ^4a ;

(k) R ^4a is H; Br; Cl; F; cyano; cyclopropyl; methylcarbonyl; methoxycarbonyl; or C _1-4 alkyl, optionally independently selected from one or more Substituting substituents of the group consisting of F and an amine group;

(l) R ^4b is H; F; methoxy; cyano; cyclopropyl; or C _1-4 alkyl, optionally exemplified by one or more groups independently selected from the group consisting of F and an amine group. Substituent substitution;

(m) R ⁵ is H; I; methoxy; 1-propen-2-yl; or C _1-6 alkyl optionally substituted by one or more methoxy substituents;

(n) R ^6a is C _1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of Ar, ethoxy, and tetrahydropyranyl; cyclopropyl; Methylcarbonyl; tetrahydropyranyl; Ar; or R ⁸ R ⁹ N-carbonyl;

(o) R ^6b is a C _2-6 alkyl group substituted with one or more F substituents; a C _1-6 alkyl group optionally arbitrarily selected from the group consisting of Ar, isopropoxy, and tetra Substituted by a substituent of the hydropyranyl group and the cyclopropyl group; a cyclopropyl group; a cyclopropyl group substituted with a phenyl substituent, the phenyl group being further substituted with one or more Cl substituents; Substituted pyrrolidinyl; NR ⁸ R ⁹ ; tetrahydropyranyl; Ar; or CH ₂ -O-Ar;

(p) wherein each Ar is independently phenyl, optionally independently selected from the group consisting of F, Cl, C _1-4 alkoxy, C _1-4 alkyl, and one or more F Substituent substitution of a group consisting of a substituted C _1-4 alkyl group; An azolyl group optionally substituted with one or more methyl substituents; or a thienyl group optionally substituted with one or more Cl substituents;

(q) each R ⁸ is methyl;

(r) each R ⁹ is methyl or 2-methyl-propyl;

(s) R ⁷ is C _1-6 alkyl optionally substituted with one or more methoxy substituents;

And pharmaceutically acceptable addition salts thereof, and solvates.

In a specific embodiment, the invention relates to a compound of formula (I) and stereoisomeric forms thereof, or any subgroup thereof as described in any other embodiment, wherein one or more, preferably All of the following restrictions:

(a) Het ¹ is a 5- or 6-membered aromatic heterocyclic ring having the formula (a-1) or (a-5); especially (a-1);

(b) R ⁰ is H or C _1-4 alkyl; especially H or methyl;

(c) R ¹ is H or C _1-4 alkyl; in particular H or methyl;

(d) X is O;

(e) R ^10a and R ^{10b are} each independently hydrogen or C _1-4 alkyl; in particular R ^10a is H and R ^10b is C _1-4 alkyl; more particularly R ^10a is H and R ^10b is methyl ;

(f) A ¹ is CR ³ or N; wherein R ³ is C _1-4 alkoxy; in particular R ³ is methoxy;

(g) A ² , A ³ and A ⁴ are CH;

(h) Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-1) or (b-2); especially (b-2);

(i) Z ¹ and Z ³ are CH;

(j) Z ² is CR ^4a ;

(k) R ^4a is H or halogen; in particular halogen; more particularly fluorine;

(l) Y ¹ and Y ³ are CH;

(m) Y ² is CR ^4b ;

(n) R ^4b is H or C _1-4 alkoxy; especially H or methoxy;

(o) R ⁵ is H or methyl; especially H;

(p) R ^6a is a C _1-6 alkyl group;

(q) R ^6b is phenyl optionally substituted by one or more halogen substituents; especially phenyl substituted by a halogen substituent; more particularly phenyl substituted by an F substituent; most particularly One F replaces a phenyl group substituted based on a para position;

(r) R ⁷ is C _1-6 alkyl; especially methyl or isopropyl;

And pharmaceutically acceptable addition salts thereof, and solvates.

In a specific embodiment, the invention relates to a novel compound of formula (I), wherein the Het ¹ is a 5-membered aromatic heterocyclic ring, having the formula (a-1), (a-2), (a-3) or (a-4)

R ⁰ is H or C _1-4 alkyl; R ¹ is H or C _1-4 alkyl; R ² is C _1-4 alkyl; X is O or S; G ¹ is CH or N; G ² is CH, N or C substituted with C _1-4 alkyl; except that G ¹ and G ^{2 are} not N at the same time; G ³ is CH or N; A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ² , A ³ and A ^{4 are} each independently CH, CF or N; only A ¹ , A ² , A ³ and A ^{4 are at} most N; Het ² is a 9-membered bicyclic aromatic group a heterocyclic ring having the formula (b-1) or (b-2):

Z ¹ is CH or N; Z ² is CR ^4a ; Z ³ is CH; Y ¹ is CH or N; Y ² is CR ^4b ; Y ³ is CH; R ^4a is H; halogen; C _1-4 alkoxy a cyano group; or a C _1-4 alkyl group optionally substituted by one or more halogen substituents; R ^4b is H; halogen; C _1-4 alkoxy; cyano; or optionally one or more a halogen substituent-substituted C _1-4 alkyl group; R ⁵ is H; halogen; cyano; or C _1-6 alkyl, optionally exemplified by one or more of each independently selected from C _1-4 alkoxy and Substituted by a substituent of the group consisting of halogen; R ^6a is a C _2-6 alkyl group substituted by one or more halogen substituents; C _1-6 alkyl group optionally optionally selected from piperidine by one or more a substituent substituted by a group consisting of Ar, C, _1-6 alkoxy, tetrahydropentanyl, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkyl; cyclo C _3-7 alkane a tetrahydropyranyl group; Ar; or CH ₂ -O-Ar; R ^6b is a C _2-6 alkyl group substituted by one or more halogen substituents; a C _1-6 alkyl group, optionally passed through a Or a plurality of each independently selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropyranyl, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkyl Substituent; ring C _{3 -7} alkyl; piperidinyl; morpholinyl; pyrrolidinyl; NR ⁸ R ⁹ ; tetrahydropyranyl; O-Ar; C _1-6 alkoxy; C _1-6 alkylthio; ; CH ₂ —O—Ar; S—Ar; NCH ₃ —Ar or NH—Ar; wherein each piperidinyl, morpholinyl, and pyrrolidinyl group may be optionally independently selected from C ₁ by one or more Substituted by a substituent group consisting of ₄ alkyl, C _2-6 alkenyl, C _1-4 alkylcarbonyl, halogen, and C _1-4 alkoxycarbonyl; wherein each Ar is independently phenyl, any One or more of each independently selected from the group consisting of halogen, C _1-4 alkoxy, cyano, NR ⁸ R ⁹ , morpholinyl, C _1-4 alkyl, and substituted with one or more halogen substituents a substituent substituted by a group consisting of C _1-4 alkyl groups; or a pyridyl group optionally arbitrarily selected from halogen, C _1-4 alkoxy, cyano, C _1-4 alkyl by one or more And substituted with a substituent consisting of a C _1-4 alkyl group substituted with one or more halogen substituents; each R ^{8 is} independently H or C _1-4 alkyl; each R ^{9 is} independently H or C _1-4 alkyl; R ⁷ is H, optionally substituted with one or more of the group consisting of substituents each independently selected from the group consisting of halogen, phenyl, and C _1-4 alkoxy The substituted C _1-6 alkyl group; and their pharmaceutically acceptable addition salts and solvates thereof.

In a specific embodiment, the invention relates to a novel compound of formula (I):

And a stereoisomeric form thereof, wherein Het ¹ is a 5-membered aromatic heterocyclic ring having the formula (a-1), (a-2), (a-3) or (a-4)

R ⁰ is H or C _1-4 alkyl; R ¹ is H or C _1-4 alkyl; R ² is C _1-4 alkyl; X is O or S; G ¹ is CH or N; G ² is CH, N or C substituted with C _1-4 alkyl; except that G ¹ and G ^{2 are} not N at the same time; G ³ is CH or N; A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ² , A ³ and A ^{4 are} each independently CH, CF or N; but no more than two of A ¹ , A ² , A ³ and A ⁴ are N; Het ² is 9 members of bicyclic aromatic Family heterocyclic ring having formula (b-1a) or (b-2a)

R ^4a is H, halogen, C _1-4 alkoxy, cyano, or optionally with one or more substituents selected from halogen substituent of the C _1-4 alkyl group; R ^4b is H, halogen, C _{1 a 4} -alkoxy group, a cyano group, or a C _1-4 alkyl group optionally substituted with one or more substituents selected from halogen; R ⁵ is H; halogen; cyano; or C _1-6 alkyl, It is optionally substituted with one or more substituents selected from C _1-4 alkoxy and halogen; R ^6a is C _2-6 alkyl substituted with one or more substituents selected from halogen; C _{1- a 6} alkyl group optionally exemplified by one or more selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropyranyl, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkane Substituent substituent; cyclo C _3-7 alkyl; tetrahydropyranyl; Ar; or CH ₂ -O-Ar; R ^6b is C _2-6 substituted with one or more substituents selected from halogen An alkyl group; a C _1-6 alkyl group optionally exemplified by one or more selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropyranyl, cyclo C _3-7 alkoxy, and cycloalkyl of C _3-7 alkyl substituents; C _3-7 cycloalkyl groups; piperidinyl; morpholinyl; pyrrolidinyl; NR ⁸ R ^9; tetrahydropyran-yl; O-Ar; C _{1- 6} alkoxy; C _1-6 alkylthio; Ar; CH ₂ -O-Ar; S-Ar; NCH ₃ -Ar or NH-Ar; wherein each piperidinyl, morpholinyl, and pyrrolidinyl group may be optionally subjected to one or more selected from C _1-4 Substituted with a substituent of an alkyl group, a C _2-6 alkenyl group, a C _1-4 alkylcarbonyl group, a halogen, and a C _1-4 alkoxycarbonyl group; wherein each Ar is independently a phenyl group, optionally passing one or more Each independently selected from the group consisting of halogen, C _1-4 alkoxy, cyano, NR ⁸ R ⁹ , morpholinyl, C _1-4 alkyl, and C _1- substituted by one or more halogen substituents Substituted with a _4- alkyl substituent; or pyridyl, optionally exemplified by one or more, each independently selected from halo, C _1-4 alkoxy, cyano, C _1-4 alkyl, and one or more Substituted with a substituent selected from a halogen substituent-substituted C _1-4 alkyl group; wherein R ⁸ is H or C _1-4 alkyl; wherein R ⁹ is H or C _1-4 alkyl; R ⁷ is H, C _{a 1-6} alkyl group optionally substituted by one or more substituents selected from the group consisting of halogen, phenyl and C _1-4 alkoxy; Z ¹ is CH or N; Y ¹ is CH or N; and Acceptable addition salts, and solvates are acceptable.

In another embodiment, the invention relates to a compound of formula (I), wherein Het ¹ is a 5-membered aromatic heterocyclic ring, having the formula (a-1), (a-2), A-3) or (a-4)

R ⁰ is H or C _1-4 alkyl; R ¹ is H or C _1-4 alkyl; R ² is C _1-4 alkyl; X is O or S; G ¹ is CH; G ² is CH, Or C substituted by C _1-4 alkyl; G ³ is CH; A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ² , A ³ and A ⁴ each Independently CH or N; only A ¹ , A ² , A ³ and A ^{4 are at} most N; Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-1) or (b-2); Z ¹ is CH or N; Z ² is CR ^4a ; Z ³ is CH; Y ¹ is CH or N; Y ² is CR _4b ; Y ³ is CH; R ^4a is H; halogen; cyano; a C _1-4 alkyl group substituted with one or more halogen substituents; R ^4b is H; halogen; cyano; or C _1-4 alkyl optionally substituted with one or more halogen substituents; R ⁵ is H Or a C _1-4 alkyl group; R ^6a is Ar; a C _2-6 alkyl group substituted with one or more halogen substituents; or a C _1-6 alkyl group, optionally independently selected from one or more Substituted by a substituent consisting of Ar, C _1-6 alkoxy, and a cyclic C _3-7 alkyl group; R ^6b is Ar; C _2-6 alkyl substituted with one or more halogen substituents; _{a 1-6} alkyl group optionally arbitrarily selected from the group consisting of Ar, C _1-6 alkoxy, and ring C _{3- a} substituent substituted by a group consisting of ₇ alkyl groups; or CH ₂ -O-Ar; wherein each Ar is independently a phenyl group, which is optionally independently selected from halogen, cyano, C _1-4 via one or more Substituted with a substituent of the group consisting of alkoxy, C _1-4 alkyl, and a C _1-4 alkyl group substituted with one or more halogen substituents; R ⁷ is a C _1-6 alkyl group, optionally Substituted by one or more substituents each independently selected from the group consisting of halogen and C _1-4 alkoxy; and pharmaceutically acceptable addition salts thereof, and solvates.

In another embodiment, the invention relates to a compound of formula (I), wherein Het ¹ is a 5-membered aromatic heterocyclic ring, having the formula (a-1), (a-2), A-3) or (a-4); R ⁰ is H or C _1-4 alkyl; R ¹ is H or C _1-4 alkyl; R ² is C _1-4 alkyl; X is O or S ; G ¹ is CH; G ² is CH or C substituted by C _1-4 alkyl; G ³ is CH; A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy A ² is CH or N; A ³ and A ⁴ are CH; Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-1) or (b-2); wherein Z ¹ is CH or N; ² is CR ^4a ; Z ³ is CH; Y ¹ is CH or N; Y ² is CR ^4b ; Y ³ is CH; R ^4a is H or halogen; R ^4b is H, halogen or optionally one or more halogen Substituent substituted C _1-4 alkyl; R ⁵ is H, or C _1-4 alkyl; R ^6a is Ar; or C _1-6 alkyl optionally substituted by one Ar; R ^6b is Ar; a C _2-6 alkyl group substituted with one or more halogen substituents; a C _1-6 alkyl group optionally substituted with one or more Ar substituents; or CH ₂ —O-Ar; wherein each Ar is independently benzene group, which is optionally substituted with one or more each independently selected from the group consisting of halogen, C _1-4 alkoxy, C _1-4 alkyl, and substituted with one or more R ⁷ is optionally substituted with one or more C _1-4 alkoxy substituents of C _1-6 alkyl;; substituents of halo C _1-4 alkyl group substituted by the group consisting of substituted and Pharmaceutically acceptable addition salts, and solvates.

In another embodiment, the invention relates to a compound of formula (I), wherein Het ¹ is a 5-membered aromatic heterocyclic ring, having the formula (a-1), (a-2), A-3) or (a-4); R ⁰ is H or methyl; R ¹ is H or methyl; R ² is methyl; X is O or S; G ¹ is CH; G ² is CH, or C substituted by methyl; G ³ is CH; A ¹ is CR ³ or N; wherein R ³ is H, F or methoxy; A ² and A ³ are CH or N; only A ¹ , A ² and A ^{3 at} most two are N; A ⁴ is CH; Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-1) or (b-2); wherein Z ¹ is CH or N; Z ² is CR ^4a Z ³ is CH; Y ¹ is CH or N; Y ² is CR ^4b ; Y ³ is CH; R ^4a is H, Br, F, cyano or CF ₃ ; R ^4b is H, F, cyano, CH ₃ or CF ₃ ; R ⁵ is H or CH ₃ ; R ^6a is Ar; ethyl; or methyl, optionally in groups of one or more independently selected from C _1-3 alkoxy and Ar Substituted by a substituent; R ^6b is Ar; 3,3,3-trifluoropropyl; cyclopropylmethyl; methyl optionally substituted with one or more Ar substituents; or CH ₂ -O-Ar; Wherein each Ar is independently a phenyl group, optionally arbitrarily selected from the group consisting of F, Cl, CN, methyl, 2 Substituted by a substituent of the group consisting of propyl, methoxy, ethoxy, and trifluoromethyl; R ⁷ is methyl, 2-propyl, tert-butyl, or optionally via a methoxy group Substituted ethyl; pharmaceutically acceptable addition salts thereof, and solvates.

In another embodiment, the invention relates to a compound of formula (I), wherein Het ¹ is a 5-membered aromatic heterocyclic ring, having the formula (a-1), (a-2), A-3) or (a-4); R ⁰ is H or methyl; R ¹ is H or methyl; R ² is methyl; X is O or S; G ¹ is CH; G ² is CH, or C substituted by methyl; G ³ is CH; A ¹ is CR ³ or N; wherein R ³ is H, F or methoxy; A ² is CH or NA ³ and A ⁴ is CH; Het ² is 9 members a bicyclic aromatic heterocyclic ring having the formula (b-1) or (b-2); wherein Z ¹ is CH or N; Z ² is CR ^4a ; Z ³ is CH; Y ¹ is CH or N; Y ² is CR ^4b ; Y ³ is CH; R ^4a is H or Br; R ^4b is H, F, CH ₃ or CF ₃ ; R ⁵ is H or CH ₃ ; R ^6a is Ar; or optionally substituted with an Ar R ^6b is Ar; 3,3,3-trifluoropropyl; cyclopropylmethyl; methyl optionally substituted by one or more Ar substituents; or CH ₂ -O-Ar; wherein each Ar Independently a phenyl group optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, methyl, 2-propyl, methoxy, ethoxy, and trifluoromethyl Substituted; R ⁷ is methyl, 2-propyl, tert-butyl, or optionally methoxy a substituted ethyl group; a pharmaceutically acceptable addition salt thereof, and a solvate.

In another embodiment, the invention relates to a compound of formula (I), wherein Het ¹ is a 5-membered aromatic heterocyclic ring, having the formula (a-1); R ⁰ is H or C _{1 -4} alkyl; R ¹ is H or C _1-4 alkyl; X is O; A ¹ is CR ³ or N; wherein R ³ is H, F or C _1-4 alkoxy; A ² , A ³ And A ⁴ is CH; Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-2); wherein Y ¹ is CH or N; Y ² is CR ^4b ; Y ³ is CH; and R ^4b is H, F Or CF ₃ ; R ^6b is phenyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, methyl, and methoxy; R ⁷ is C _1-4 alkyl; And pharmaceutically acceptable addition salts thereof, and solvates.

In another embodiment, the invention relates to a compound of formula (I), wherein Het ¹ is a 5-membered aromatic heterocyclic ring, having the formula (a-1); R ⁰ is H or C _{1 -4} alkyl; R ¹ is H or C _1-4 alkyl; X is O; A ¹ is CR ³ ; wherein R ³ is C _1-4 alkoxy; A ² , A ³ and A ⁴ are CH; Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-2); wherein Y ¹ is CH; Y ² is CH; Y ³ is CH; and R ^6b is optionally substituted by one or more halogen substituents. Phenyl; R ⁷ is C _1-4 alkyl; and pharmaceutically acceptable addition salts thereof, and solvates.

In another embodiment, the invention relates to any other embodiment, wherein R ^6a is C _2-6 alkyl substituted with one or more halo substituents; C _1-6 alkyl, optionally Substituting one or more substituents independently selected from the group consisting of Ar, C _1-6 alkoxy, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkyl; Ar; or CH ₂ -O-Ar; wherein each Ar is independently phenyl, which is optionally independently selected from halo, C _1-4 alkoxy, cyano, C _1-4 alkyl, and one through one or more Or a substituent substituted by a group consisting of a plurality of halogen substituent-substituted C _1-4 alkyl groups.

In another embodiment, the invention relates to any other embodiment, wherein R ^6b is C _2-6 alkyl substituted with one or more halo substituents; C _1-6 alkyl, any Substituting one or more substituents independently selected from the group consisting of Ar, C _1-6 alkoxy, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkyl; Ar; or CH ₂ -O-Ar; wherein each Ar is independently phenyl, which is optionally independently selected from halo, C _1-4 alkoxy, cyano, C _1-4 alkyl, and one through one or more Or a substituent substituted by a group consisting of a plurality of halogen substituent-substituted C _1-4 alkyl groups.

In another embodiment, the invention relates to any other embodiment, wherein R ^6a is isobutyl; cyclopropylmethyl; 3,3,3-trifluoropropyl; substituted by methoxy a C _2-4 alkyl group; CH ₂ -O-Ar; or Ar; wherein each Ar is independently a phenyl group, optionally exemplified by one or more of each independently selected from the group consisting of halogen, C _1-4 alkoxy, cyanide group, C _1-4 alkyl, halo, and substituted with one or more substituents of the group consisting of C _1-4 alkyl group substituted by the substituents.

In another embodiment, the invention relates to a compound of any other embodiment, wherein R ^6b is isobutyl; cyclopropylmethyl; 3,3,3-trifluoropropyl; substituted by methoxy a C _2-4 alkyl group; CH ₂ -O-Ar; or Ar; wherein each Ar is independently a phenyl group, optionally exemplified by one or more of each independently selected from the group consisting of halogen, C _1-4 alkoxy, cyanide group, C _1-4 alkyl, halo, and substituted with one or more substituents of the group consisting of C _1-4 alkyl group substituted by the substituents.

In another embodiment, the invention is directed to any other embodiment of the invention, wherein R ^6a is Ar; wherein each Ar is independently phenyl, optionally independently selected from halo, C by one or more _C1-4 alkoxy, cyano, C _1-4 alkyl, halo, and substituted with one or more substituents of the group consisting of C _1-4 alkyl group substituted by the substituents.

In another embodiment, the invention relates to any other embodiment, wherein R ^6a is C _2-6 alkyl substituted with one or more halo substituents; or phenyl, optionally through one each independently selected from the group consisting of one or more of halogen, C _1-4 alkoxy, C _1-4 alkyl, and substituted with one or more halogen substituents of the group consisting of C _1-4 alkyl group substituted with the substituent group; In particular, a phenyl group is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, methoxy, methyl, and trifluoromethyl.

In another embodiment, the invention is directed to the compound of any other embodiment, wherein R ^6b is Ar; wherein each Ar is independently phenyl, optionally independently selected from halo, C by one or more _C1-4 alkoxy, cyano, C _1-4 alkyl, halo, and substituted with one or more substituents of the group consisting of C _1-4 alkyl group substituted by the substituents.

In another embodiment, the invention relates to any other embodiment, wherein R ^6b is C _2-6 alkyl substituted with one or more halo substituents; or phenyl, optionally through one each independently selected from the group consisting of one or more of halogen, C _1-4 alkoxy, C _1-4 alkyl, halo, and substituted with one or more substituents of the group consisting of C _1-4 alkyl group substituted with the substituent group; Particularly a C _2-6 alkyl group substituted with one or more halogen substituents; or a phenyl group, optionally exemplified by one or more of each independently selected from the group consisting of halogen, methoxy, methyl, and trifluoromethyl Substituents substituted for the group are substituted.

In another embodiment, the invention relates to any other embodiment, wherein R ^4a is H, halogen, C _1-4 alkoxy, or optionally substituted with one or more halogen substituents Base; especially H or halogen; more particularly H or F.

In another embodiment, the invention is directed to any other embodiment of the invention, wherein R ^4a is H, halo, methyl, cyano or trifluoromethyl.

In another embodiment, the invention relates to a compound of any other embodiment, wherein R ^4b is H, halogen, C _1-4 alkoxy, or optionally substituted with one or more halogen substituents a group; especially H, halogen or C _1-4 alkoxy; more particularly H, F or methoxy.

In another embodiment, the invention is directed to a compound of any other embodiment, wherein R ^4b is H, halo, methyl, cyano or trifluoromethyl.

In another embodiment, the invention relates to any other embodiment, wherein R ⁷ is C _1-6 alkyl, optionally substituted by one or more groups independently selected from the group consisting of halogen Substituted, and C _1-4 alkoxy.

In another particular embodiment, the present invention relates to any other compound of Example particular embodiment, wherein R ⁷ is C _1-4 alkyl.

In another particular embodiment, the present invention relates to any other compound of Example particular embodiment, wherein R ⁸ is H or C _1-4 alkyl; and wherein R ⁹ is H or C _1-4 alkyl.

In a particular embodiment, the present invention relates to any other particular embodiment of the compound of Example, wherein R ⁵ is H or methyl; R ^6a is a phenyl group substituted by inter position, and optionally further substituted at other positions.

In a particular embodiment, the present invention relates to any other compound of Example particular embodiment, wherein R ⁵ is H or methyl; phenyl is substituted with R ^6a via the ortho position, and optionally further substituted at other positions.

In a particular embodiment, the present invention relates to any other particular embodiment of the compound of Example, wherein R ⁵ is H or methyl; R ^6a is a para-substituted by the phenyl group, and optionally further substituted at other positions.

In a particular embodiment, the invention relates to a compound of any other embodiment, wherein R ⁵ is H or methyl; R ^6a is phenyl substituted in the para position by F, and is optionally further substituted at other positions .

In a particular embodiment, the invention relates to any other embodiment of the invention, wherein R ⁵ is H; R ^6a is phenyl substituted methyl, wherein phenyl is optionally independently selected from one or more halo, C _1-4 alkoxy, cyano, NR ⁸ R ^9, morpholinyl, C _1-4 alkyl, halo, and substituted with one or more substituents of the group consisting of C _1-4 alkyl The substituent is substituted.

In a particular embodiment, the invention is directed to any other embodiment of the invention, wherein R ^6b is a meta-substituted phenyl group, and is optionally further substituted at other positions.

In a particular embodiment, the invention is directed to any other embodiment of the invention, wherein R ^6b is ortho-substituted phenyl, and is optionally further substituted at other positions.

In a particular embodiment, the invention is directed to any other embodiment of the invention, wherein R ^6b is para-substituted phenyl, and is optionally further substituted at other positions.

In a particular embodiment, the invention is directed to a compound of any other embodiment, wherein R ^6b is phenyl substituted with F in the para position, and is optionally further substituted at other positions.

In a particular embodiment, the invention relates to any other embodiment of the invention, wherein R ^6b is phenyl substituted methyl, wherein phenyl is optionally exemplified by one or more independently selected from halo, C _{1 -4} alkoxy, cyano, NR ⁸ R ^9, morpholinyl, C _1-4 alkyl, and substituted with one or more halo substituents consisting of C _1-4 alkyl group substituted with the substituent group .

In a particular embodiment, the present invention relates to any other compound of Example particular embodiment, one in which R ⁰ and R ¹ are as C _1-4 alkyl, and R ⁰ and R ¹ are one is H; in particular one of R ⁰ and R ¹ are methyl, and one of R ⁰ and R ¹ is H. by

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein X is O.

In other specific embodiments, the invention is directed to any other embodiment of the invention, wherein Het ¹ is (a-1) and X is O.

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein X is S.

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Het ¹ is (a-1) and X is S.

In other specific embodiments, the invention relates to compounds of any other embodiment, wherein A ¹ is CR ³ or N; wherein R ³ is H, F or methoxy.

In a specific embodiment that follows, the invention relates to any other embodiment of the invention, wherein A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; especially R ³ is H, F or C _1-4 alkoxy; more particularly R ³ is H, F or methoxy; most particularly R ³ is methoxy; A ² is CH, CF or N; especially CH or N ; A ³ and A ⁴ are CH or N; only A ¹ , A ² , A ³ and A ^{4 are at} most N.

In a specific embodiment after, the present invention relates to any other particular embodiment of the compound of Example, wherein A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ² is CH, CF or N; in particular CH or CF; more in particular CH; A ³ and A ⁴ is CH.

In the following specific examples, the invention is directed to compounds of any other particular embodiment wherein A ¹ is N and A ² is CH.

In a specific embodiment that follows, the invention relates to compounds of any other specific embodiment, wherein when A ¹ is N, A ² is CH.

In a specific embodiment that follows, the invention is directed to any other embodiment of the invention, wherein at most one of A ¹ , A ² , A ³ and A ⁴ is N.

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Het ¹ has the formula (a-1).

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Het ¹ has formula (a-2).

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Het ¹ has formula (a-3).

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Het ¹ has formula (a-4).

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Het ¹ has the formula (a-5).

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Het ² has formula (b-1).

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Het ² has formula (b-2).

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Y ¹ is CH.

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein Y ¹ is N.

In other embodiments, the present invention relates to any other particular embodiment of the compound of Example, wherein Z ¹ is CH.

In other embodiments, the present invention relates to any other particular embodiment of the compound of Example, wherein Z ¹ is N.

In other specific embodiments, the invention is directed to compounds of any other embodiment, wherein Z ² is CR ^4a .

In other specific embodiments, the invention is directed to compounds of any other embodiment, wherein Z ² is N.

In other specific embodiments, the invention is directed to a compound of any other embodiment, wherein one of Z ² and Z ³ is N, or wherein one of Y ² and Y ³ is N.

In other specific embodiments, the invention is directed to compounds of any other particular embodiment, wherein _C1-6 alkyl is defined as _C1-4 alkyl.

In a particular embodiment, the compound is of formula (I) is selected from the group comprising the following: 2- (4-fluorophenyl) - N - [3- methoxy-4- (5 Azyl)phenyl]-imidazo[1,2- a ]pyridine-8-amine, N- [4-(2,4-dimethyl-5- Azyl)-3-methoxyphenyl]-2-(4-fluorophenyl)-imidazo[1,2- a ]pyridine-8-amine, N- [4-(2,4-dimethyl Base-5- Oxadiazol-yl) -3-methoxyphenyl] -3-methyl-2-phenyl - imidazo [1,2- a] pyridin-8-amine, 2- (4-fluorophenyl) - N - [3-methoxy-4-(4-methyl-5- Thiazolyl) phenyl] - and imidazo [1,2- a] pyridin-8-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (4-methyl-5 - Thiazolyl) phenyl] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (1-methyl - 1 H -pyrazol-4-yl)phenyl]-1-methyl-1 H -benzimidazole-4-amine, N- [4-(2,4-dimethyl-5-thiazolyl)- 3-methoxyphenyl]-2-(3-methoxyphenyl)-3-methyl-imidazo[1,2- a ]pyridine-8-amine, N -[4-(1,3 -Dimethyl-1 H -pyrazol-4-yl)-3-methoxyphenyl]-2-(3-methoxyphenyl)-3-methyl-imidazo[1,2- a Pyridine-8-amine, N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-(3-methoxyphenyl)-3-methyl-imidazo[1,2- a ]pyridine-8-amine, N- [3-methoxy-4- (2-methyl-5-thiazolyl)phenyl]-2-(3-methoxyphenyl)-3-methyl-imidazo[1,2- a ]pyridine-8-amine, N -[ 4-(2,4-dimethyl-5- Azyl)-3-methoxyphenyl]-2-(4-fluorophenyl)-1-methyl-1 H -benzimidazole-4-amine, 2-(4-fluorophenyl) -N -[3-methoxy-4-(1-methyl-1 H -pyrazol-5-yl)phenyl]-1-methyl-1 H -benzimidazole-4-amine, 2-(4 -fluorophenyl) -N- [3-methoxy-4-(3-methyl-1,2,4- Oxadiazol-5-yl) phenyl] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2 -methyl-5- Azyl)phenyl]-1-methyl-1 H -benzimidazole-4-amine, 2-(4-fluorophenyl)-1-methyl- N- [5-(4-methyl-5 - Azyl)-2-pyridyl]-1 H -benzimidazol-4-amine, N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-1-methyl-2-(3,3,3-trifluoropropyl)-1 H -benzimidazole-4-amine, N- [3-methoxy-4-( 4-methyl-5- Azyl)phenyl]-2-(3-methoxyphenyl)-1-methyl-1 H -benzimidazole-4-amine, 2-(3-chlorophenyl)-1-methyl- N -[5-(4-methyl-5- Azyl)-2-pyridyl]-1 H -benzimidazol-4-amine, 2-(4-chloro-3-methoxyphenyl)-1-methyl- N- [5-(4- Methyl-5- Azyl)-2-pyridyl]-1 H -benzimidazol-4-amine, 2-[4-ethoxy-2-methyl-5-(1-methylethyl)phenyl] -N -[3-methoxy-4-(4-methyl-5- Thiazolyl) phenyl] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2-methyl - 5- Thiazolyl) phenyl] - and imidazo [1,2- a] pyridin-8-amine, 2- (4-fluorophenyl) - N - [4- (2- methyl-5- Thiazolyl) phenyl] - and imidazo [1,2- a] pyridin-8-amine, 1- (1,1-dimethylethyl) -2- (4-fluorophenyl) - N - [6 -(4-methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 2-(4-fluorophenyl)-1-methyl- N- [6-(4-methyl-5- Oxadiazol-yl) -3-pyridinyl] -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) -1- (1-methylethyl) - N - [4- (2- Methyl-5- Azyl)phenyl]-1 H -benzimidazol-4-amine, N- [4-(2-methyl-5- Thiazolyl) phenyl] -2- (2-methyl-phenyl) - imidazo [1,2-a] pyridin-8-amine, 2- (4-fluoro-2-methylphenyl) - N - [6-(4-methyl-5- Thiazolyl) -3-pyridinyl] - and imidazo [1,2-a] pyridin-8-amine, 2- (2-fluoro-4-methylphenyl) - N - [6- (4- Methyl -5- Azyl)-3-pyridyl]-imidazo[1,2-a]pyridine-8-amine, N- [4-(2-methyl-5- Azyl)phenyl]-2-[2-methyl-5-(trifluoromethyl)phenyl]-imidazo[1,2-a]pyridin-8-amine, 2-(2,4-di fluorophenyl) - N - [3- methoxy-4- (2-methyl-5- Thiazolyl) phenyl] -1-methyl -1 H - imidazo [4,5- c] pyridin-4-amine, 1- (2-methoxyethyl) - N - [3- methoxy 4-(2-methyl-5-thiazolyl)phenyl]-2-methyl-1 H -benzimidazol-4-amine, N- [3-methoxy-4-(2-methyl) -5-thiazolyl)phenyl]-2-(2-methylphenyl)-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluorophenyl)-1-methyl - N -[4-(2-methyl-5- Thiazolyl) phenyl] -1 H - imidazo [4,5- c] pyridin-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2- Base-5- Thiazolyl) phenyl] -1- (1-methylethyl) -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2-methyl-5- Thiazolyl) phenyl] -1-methyl -1H- imidazo [4,5- c] pyridin-4-amine, 2- (4-fluoro-2-methylphenyl) - N - [4- ( 2-methyl-5- Thiazolyl) phenyl] - and imidazo [1,2-a] pyridin-8-amine, 2- (2-fluoro-4-methylphenyl) - N - [4- (2- methyl-5- Azyl)phenyl]-imidazo[1,2-a]pyridine-8-amine, 2-(4-fluorophenyl)-1-methyl- N- [6-(2-methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 2-(2-chlorophenyl)-3-methyl- N- [4-(2-methyl-5- Thiazolyl) phenyl] - and imidazo [1,2-a] pyridin-8-amine, 2- (5-methoxy-2-methylphenyl) - N - [4- (2- methyl - 5- Thiazolyl) phenyl] - and imidazo [1,2-a] pyridin-8-amine, 2 - [(4-fluorophenyl) methyl] - N - [4- (2- methyl-5- Azyl)phenyl]-imidazo[1,2-a]pyridine-8-amine, N- [3-fluoro-4-(2-methyl-5- Azyl)phenyl]-2-(4-fluorophenyl)-1-methyl-1 H -imidazo[4,5-c]pyridin-4-amine, 2-(5-fluoro-2-methyl phenyl) - N - [3- methoxy-4- (2-methyl-5- Azyl)phenyl]-imidazo[1,2-a]pyridine-8-amine, N- [6-(4-methyl-5- Azyl)-3-pyridyl]-2-[2-methyl-5-(trifluoromethyl)phenyl]-imidazo[1,2-a]pyridin-8-amine, 2-(3- methoxyphenyl) -1- (1-methylethyl) - N - [4- (2- methyl-5- Thiazolyl) phenyl] -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) -1- (1-methylethyl) - N - [5- (2- methyl - 5- Thiazolyl) -2-pyridinyl] -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2-methyl-5- Azyl)phenyl]-1-methyl-6-(trifluoromethyl)-1 H -benzimidazole-4-amine, 2-(4-fluorophenyl)-1-(1-methyl Base)-N-[4-(2-methyl-5- Thiazolyl) phenyl] -1 H - imidazo [4,5-c] pyridin-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2- Base-5- Azyl)phenyl]-1-(1-methylethyl)-1 H -imidazo[4,5- c ]pyridin-4-amine, N- [3-fluoro-4-(2-methyl) -5- Azyl)phenyl]-2-(5-methoxy-2-methylphenyl)-imidazo[1,2- a ]pyridine-8-amine, N- [3-fluoro-4-(2 -methyl-5- Azyl)phenyl]-2-(4-fluorophenyl)-1-(1-methylethyl)-1 H -benzimidazole-4-amine, 2-(4-fluorophenyl)-1 - (1-methylethyl) - N - [6- (2- methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 2-(2,4-difluorophenyl)-1-methyl- N- [4-(2-methyl- 5- Thiazolyl) phenyl] -1 H - imidazo [4,5- c] pyridin-4-amine, 2- (2,4-difluorophenyl) - N - [3- methoxy-4- ( 4-methyl-5- Thiazolyl) phenyl] -1-methyl -1H- imidazo [4,5- c] pyridin-4-amine, 2- (2,4-difluorophenyl) - N - [3- fluoro-4 -(2-methyl-5- Azyl)phenyl]-1-methyl-1 H -imidazo[4,5- c ]pyridin-4-amine, 6-fluoro-2-(3-methoxyphenyl)-1-methyl - N -[4-(2-methyl-5- Thiazolyl) phenyl] -1 H - benzimidazol-4-amine, 2- (4-fluoro-2-methylphenyl) - N - [4- (2- methyl-5- Azolyl)phenyl]-imidazo[1,2- a ]pyridyl -8-amine, 2-(4-fluorophenyl)-1,6-dimethyl- N- [4-(2-methyl-5- Thiazolyl) phenyl] -1 H - imidazo [4,5- c] pyridin-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2- Base-5- Azyl)phenyl]-1,6-dimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine, 6-bromo-2-(4-fluoro-2-methylphenyl ) -N -[4-(2-methyl-5- Azolyl)phenyl]-imidazo[1,2- a ]pyridyl -8-amine, 1-methyl- N- [6-(4-methyl-5- Oxadiazol-yl) -3-pyridinyl] -2- (phenoxymethyl) -1 H - benzimidazol-4-amine, 2- (4-chloro-3-methoxyphenyl) - N - [ 3-methoxy-4-(2-methyl-5- Azyl)phenyl]-1-methyl-1 H -benzimidazol-4-amine, N- [3-methoxy-4-(2-methyl-5- Azyl)phenyl]-2-(3-methoxyphenyl)-1-methyl-1 H -benzimidazole-4-amine, 2-(cyclopropylmethyl)-1-ethyl- N -[3-methoxy-4-(2-methyl-5- Azyl)phenyl]-1 H -benzimidazol-4-amine, N- [3-fluoro-4-(4-methyl-5- Azyl)phenyl]-2-(4-fluorophenyl)-1-(1-methylethyl)-1 H -benzimidazole-4-amine, 2-(cyclopropylmethyl) -N -[3-fluoro-4-(2-methyl-5- Thiazolyl) phenyl] -1-methyl -1 H - imidazo [4,5- c] pyridin-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4 -(2-methyl-5-thiazolyl)phenyl]-1-(1-methylethyl)-1 H -benzimidazole-4-amine, N- [3-fluoro-4-(2- Methyl-5- Azyl)phenyl]-2-(3-methoxyphenyl)-1-methyl-1 H -imidazo[4,5- c ]pyridin-4-amine, 2-(2,4-di fluorophenyl) - N - [3- methoxy-4- (2-methyl-5-thiazolyl) phenyl] -1-methyl -1 H - imidazo [4,5- c] pyridin - 4-amine, N- [3-fluoro-4-(2-methyl-5- Azyl)phenyl]-2-(4-fluorophenyl)-3-methyl- 3H -imidazo[4,5- b ]pyridine-7-amine, N- [3-methoxy-4 -(4-methyl-5- Azyl)phenyl]-1-methyl-6-(trifluoromethyl)-2-(3,3,3-trifluoropropyl)-1 H -benzimidazole-4-amine, N -[ 3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-methyl-6-(trifluoromethyl)-imidazo[1,2-a]pyridin-8-amine, 2-(4-fluorophenyl)-1-methyl - N- [4-(1-methyl-1 H -pyrazol-4-yl)phenyl]-1 H -benzimidazol-4-amine, 8-[[3-fluoro-4-(2- Methyl-5- Azyl)phenyl]amino] -N , N -dimethyl-6-(trifluoromethyl)-imidazo[1,2- a ]pyridine-2-carboxamide, 6-fluoro-2- (3-methoxyphenyl)-1-methyl- N- [6-(2-methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2,3-dimethyl-6-(trifluoromethyl)-imidazo[1,2- a ]pyridine-8-amine, N- [3-methoxy-4- (2-methyl-5- Azyl)phenyl]-2-methyl-6-(trifluoromethyl)-imidazo[1,2- a ]pyridyl -8-amine, 6-bromo-2-methyl- N- [4-(2-methyl-5- Azolyl)phenyl]-imidazo[1,2- a ]pyridyl -8-amine, 8-[[3-methoxy-4-(4-methyl-5-) Azolyl)phenyl]amino] -N , N -dimethyl-6-(trifluoromethyl)-imidazo[1,2- a ]pyridine-2-carboxamide, 2-(4-fluoro Phenyl)-1-methyl- N- [6-(2-methyl-5- Azyl)-3-pyridyl]-6-(trifluoromethyl)-1 H -benzimidazole-4-amine, 1-methyl-2-[(1-methylethoxy)methyl] - N -[4-(2-methyl-5- Azyl)phenyl]-1 H -benzimidazol-4-amine, 2-(4-fluorophenyl)-1-methyl- N- [6-(1-methyl-1 H -pyrazole- 4-yl)-3-pyridyl]-1 H -benzimidazol-4-amine, 2,3-dimethyl- N- [4-[2-(1-methylethyl)-5- Azolyl]phenyl]-imidazo[1,2- a ]pyridine-8-amine, N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2,3-dimethyl-imidazo[1,2- a ]pyridine-8-amine, 1-[8-[[3-methoxy-4-(4-methyl) -5- Azyl)phenyl]amino]-6-(trifluoromethyl)imidazo[1,2- a ]pyridin-2-yl]-ethanone, N- [3-methoxy-4-(2 -methyl-5- Azyl)phenyl]-1-methyl-2-(3,3,3-trifluoropropyl)-1 H -imidazo[4,5- c ]pyridin-4-amine, 2-(4- fluorophenyl) - N - [3- methoxy-4- (4-methyl-5- Azyl)phenyl]-1,6-dimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine, 8-[[3-methoxy-4-(4-methyl) -5- Azyl)phenyl]amino]-2-methyl-imidazo[1,2- a ]pyridine-6-carbonitrile, N- [3-methoxy-4-(2-methyl-5- Azyl)phenyl]-2-methyl-6-(trifluoromethyl)-imidazo[1,2- b ]嗒 -8-amine, N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-methyl-6-(trifluoromethyl)-imidazo[1,2- b ]嗒 -8-amine, 6-fluoro- N- [3-methoxy-4-(2-methyl-5- Thiazolyl) phenyl] -1-methyl-2- (1-pyrrolidinyl) -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy 4-(1-methyl-1 H -1,2,4-triazol-5-yl)phenyl]-1-methyl-1H-benzimidazole-4-amine, 6-fluoro-1 -methyl- N- [4-(2-methyl-5- Thiazolyl) phenyl] -2- (1-pyrrolidinyl) -1 H - benzimidazol-4-amine, 6-fluoro-2- (4-fluoro-2-methylphenyl) - N - [ 3-methoxy-4-(4-methyl-5- Azyl)phenyl]-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluoro-2-methylphenyl)-8-[[3-methoxy-4-( 4-methyl-5- Thiazolyl) phenyl] amino] - and imidazo [1,2- a] pyridine-6-carbonitrile, 2- (4-fluorophenyl) - N - [3- methoxy-4- (4- Methyl-5- Thiazolyl) phenyl] -3-methyl -3 H - imidazo [4,5- c] pyridin-7-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4 -(2-methyl-5- Azyl)phenyl]-3-methyl- 3H -imidazo[4,5- c ]pyridine-7-amine, N- [3-methoxy-4-(2-methyl-5- Azyl)phenyl]-2-(3-methoxyphenyl)-1,6-dimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine, 1-methyl- 2-(4-methyl-5- Thiazolyl) - N - [4- (2- methyl-5- Azyl)phenyl]-6-(trifluoromethyl)-1 H -benzimidazol-4-amine, 2-(3-methoxyphenyl)-1,6-dimethyl- N- [ 4-(2-methyl-5- Azyl)phenyl]-1 H -imidazo[4,5- c ]pyridin-4-amine, 2-(4-fluorophenyl)-1-methyl- N- [5-(2-methyl -5- Azyl)-2-pyrimidinyl]-1 H -benzimidazol-4-amine, N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-(3-methoxyphenyl)-1,6-dimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine, 2-(3- Methoxyphenyl)-1-methyl-4-[[6-(2-methyl-5-) Azyl)-3-pyridyl]amino]-1 H -benzimidazole-6-carbonitrile, N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-methyl-imidazo[1,2- a ]pyridyl -8-amine, 6-fluoro- N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-(2-methylpropyl)-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluorophenyl)-7-[[3- Oxy-4-(2-methyl-5- Azyl)phenyl]amino]-3-methyl- 3H -imidazo[4,5- b ]pyridine-5-carbonitrile, 1-methyl- N- [4-(2-methyl- 5- Azyl)phenyl]-2-(tetrahydro-2 H -piperidin-4-yl)-6-(trifluoromethyl)-1 H -benzimidazole-4-amine, 2-(4-fluoro Phenyl)-1-methyl- N- [4-(1-methyl-1 H -pyrazol-5-yl)phenyl]-1 H -benzimidazole-4-amine, 2-(4- Fluorophenyl)-6-methoxy- N- [3-methoxy-4-(2-methyl-5- Azyl)phenyl]-1-methyl-1 H -benzimidazol-4-amine, N- [3-methoxy-4-(2-methyl-5- Azyl)phenyl]-1-(1-methylethyl)-2-(tetrahydro-2 H -pyran-4-yl)-1 H -benzimidazole-4-amine, 2-(4 - fluorophenyl) - N - [3- methoxy-4- (2-methyl-5- Azyl)phenyl]-3,5-dimethyl- 3H -imidazo[4,5- b ]pyridine-7-amine, 4-[[3-methoxy-4-(4-methyl) -5- Azyl)phenyl]amino]-2-(3-methoxyphenyl)-1-methyl-1 H -benzimidazole-6-carbonitrile, 2-(4-fluorophenyl)-1 -methyl- N- [5-(1-methyl-1 H -pyrazol-5-yl)-2-pyridyl]-1 H -benzimidazole-4-amine, 2-(ethoxymethyl) yl) - N - [3- methoxy-4- (4-methyl-5- Azyl)phenyl]-6-(trifluoromethyl)-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluoro-2-methylphenyl)-8-[[ 3-methoxy-4-(4-methyl-5- Azyl)phenyl]amino]-imidazo[1,2- a ]pyridine-6-methylamine, N- [3-methoxy-4-(2-methyl-5- Azyl)phenyl]-1,6-dimethyl-2-(tetrahydro-2 H -piperidin-4-yl)-1 H -imidazo[4,5- c ]pyridin-4-amine, 5-cyclopropyl-2- (4-fluorophenyl) - N - [3- methoxy-4- (2-methyl-5- Azyl)phenyl]-3-methyl- 3H -imidazo[4,5- b ]pyridine-7-amine, 2-(4-fluorophenyl)-3-(1-methylvinyl) - N -[4-(2-methyl-5- Thiazolyl) phenyl] - and imidazo [1,2- a] pyridin-8-amine, 6-cyclopropyl-2- (4-fluorophenyl) - N - [3- methoxy-4- ( 2-methyl-5- Azyl)phenyl]-1-methyl-1 H -imidazo[4,5- c ]pyridin-4-amine, 2-(4-fluorophenyl)-3-(1-methylethyl) - N -[4-(2-methyl-5- Azyl)phenyl]-imidazole [1,2- a ]pyridine-8-amine, 2-(4-fluorophenyl)-4-[[3-methoxy-4-(4-methyl-5) - Azyl)phenyl]amino]-1-methyl-1 H -benzimidazole-6-carbonitrile, 8-[[3-methoxy-4-(4-methyl-5-) Azyl)phenyl]amino]-2-(2-methylpropyl)-imidazo[1,2- a ]pyridine-6-carbonitrile, N- [3-methoxy-4-(2 -methyl-5- Azyl)phenyl]-1,6-dimethyl-2-[3-(1-methylethoxy)phenyl]-1 H -imidazo[4,5- c ]pyridin-4-amine ,6-fluoro- N- [4-(2-methyl-5- 4-yl)phenyl]-2-(2-methylpropyl)-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluorophenyl)-1-methyl- N- [6-(2-Methyl-5-thiazolyl)-3-pyridyl]-1 H -benzimidazole-4-amine, 6-fluoro-2-(4-fluoro-2-methylphenyl) - N -[4-(2-methyl-5- Thiazolyl) phenyl] - and imidazo [1,2- a] pyridin-8-amine, 2- (4-fluoro-2-methylphenyl) - N - [3- methoxy-4- (4 -methyl-5- Azyl)phenyl]-6-methyl-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluorophenyl)-1-methyl- N- [4-(4- Methyl-5- Azyl)phenyl]-1H-benzimidazol-4-amine, 2-(3-methoxyphenyl)-3-methyl- N- [4-(4-methyl-5- Azyl)phenyl]-imidazo[1,2- a ]pyridine-8-amine, 6-fluoro- N ⁴ -[3-methoxy-4-(2-methyl-5- Azyl)phenyl] -N ² ,1-dimethyl- N ² -(2-methylpropyl)-1 H -benzimidazole-2,4-diamine, N- [3-methoxy -4-(4-methyl-5- Azyl)phenyl]-2-(tetrahydro-2 H -piperidin-4-yl)-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluorophenyl)-4 -[[3-methoxy-4-(4-methyl-5- Azyl)phenyl]amino]-1-methyl-1 H -benzimidazole-6-methylamine, N- [6-(4-methyl-5- Azyl)-3-pyridyl]-2-(tetrahydro-2 H -pyran-4-yl)-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluorophenyl )-1-methyl-4-[[6-(4-methyl-5-) Azyl)-3-pyridyl]amino]-1 H -benzimidazole-6-carbonitrile, 6-cyclopropyl- N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-methyl-imidazo[1,2- a ]pyridyl 8-amine, 2- (3-chlorophenyl) -1- (1-methylethyl) - N - [6- (4- methyl-5- Oxadiazol-yl) -3-pyridinyl] -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) -1- (1-methylethyl) - N - [6- (4- Methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 2-(2-chlorophenyl)-6-fluoro-1-methyl- N- [6-(4-methyl -5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 2-(2-chlorophenyl)-1-methyl- N- [6-(4-methyl-5- Azyl)-3-pyridyl]-1 H -imidazo[4,5- c ]pyridin-4-amine, N- [4-(2,4-dimethyl-5- Azyl)phenyl]-2-(4-fluorophenyl)-1-methyl-1 H -benzimidazole-4-amine, 2-(4-fluorophenyl)-1-methyl-4- [[6-(2-methyl-5-) Oxadiazol-yl) -3- pyridinyl] amino] -1 H - benzimidazole-6-carbonitrile, 6-fluoro-2- (4-fluoro-2-methylphenyl) - N - [6- ( 2-methyl-5- Azyl)-3-pyridyl]-imidazo[1,2- a ]pyridine-8-amine, 2-(2-chlorophenyl)-1-methyl- N- [6-(2-methyl -5- Oxadiazol-yl) -3-pyridinyl] -1 H - imidazo [4,5- c] pyridin-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- ( 2-methyl-5- Thiazolyl) phenyl] -3-methyl-5- (1-methylethyl) -3 H - imidazo [4,5- b] pyridin-7-amine, 6-fluoro-2- (4- Fluorophenyl)-1-methyl- N- [6-(4-methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 6-fluoro-2-(4-fluorophenyl)-1-methyl- N- [6-(2-methyl -5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 2-(2-chlorophenyl)-6-fluoro-1-methyl- N- [6-(2-methyl -5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 6-chloro- N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-(tetrahydro-2 H -piperidin-4-yl)-imidazo[1,2- a ]pyridine-8-amine, 2-(5-chloro-2-thienyl ) -1- (1-methylethyl) - N - [6- (4- methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, N- [6-(2,4-dimethyl-5- Azyl)-3-pyridyl]-2-(4-fluorophenyl)-1-(1-methylethyl)-1 H -benzimidazole-4-amine, 2-(2-chlorophenyl ) -N -[6-(2,4-dimethyl-5- Azyl)-3-pyridyl]-6-fluoro-1-methyl-1 H -benzimidazol-4-amine, N- [3-methoxy-4-(2-methyl-5- Azyl)phenyl]-3-(3-methoxypropyl)-2-[2-(trifluoromethyl)phenyl]-imidazo[1,2- a ]pyridine-8-amine, 2 -(4-fluorophenyl)-3-methyl- N- [6-(2-methyl-5- Azyl)-3-pyridyl]-3 H -imidazo[4,5- c ]pyridine-7-amine, 2-(4-fluorophenyl)-3-iodo- N- [4-(2- Methyl-5- Azyl)phenyl]-imidazo[1,2- a ]pyridine-8-amine, 3-methyl- N- [6-(2-methyl-5- Azyl)-3-pyridyl]-2-[2-(trifluoromethyl)phenyl]-imidazo[1,2- a ]pyridine-8-amine, 8-[[3-methoxy- 4-(4-methyl-5- Methylzolyl)phenyl]amino]-2-(2-methylpropyl)-imidazo[1,2- a ]pyridine-6-carboxylic acid methyl ester, N- [4-(2,4-di Methyl-5- Azyl)-3-methoxyphenyl]-2-(4-fluorophenyl)-1-(1-methylethyl)-1 H -benzimidazole-4-amine, N- [4- (2,4-dimethyl-5- Azyl)phenyl]-2-(4-fluorophenyl)-1-(1-methylethyl)-1 H -benzimidazole-4-amine, 2-cyclopropyl- N- [6- (4-methyl-5- Azyl)-3-pyridyl]-imidazo[1,2- a ]pyridine-8-amine, 2-cyclopropyl- N- [4-(2-methyl-5- Thiazolyl) phenyl] - and imidazo [1,2- a] pyridin-8-amine, 6-fluoro-2- (4-fluorophenyl) -1- (1-methylethyl) - N - [ 6-(2-methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 6-fluoro- N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-(tetrahydro-2 H -piperidin-4-yl)-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluorophenyl)-3 - (methoxymethyl) - N - [3- methoxy-4- (2-methyl-5- Azyl)phenyl]-imidazo[1,2- a ]pyridine-8-amine, 2-[1-(4-chlorophenyl)cyclopropyl]-1-methyl- N- [6-( 2-methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, N- [6-(4-methyl-5- Azyl)-3-pyridyl]-2-[(tetrahydro-2 H -piperidin-4-yl)methyl]-imidazo[1,2- a ]pyridine-8-amine, 2-[1 -(4-chlorophenyl)ethyl]-1-methyl- N- [6-(2-methyl-5- Oxadiazol-yl) -3-pyridinyl] -1 H - benzimidazol-4-amine, 2- (2-chlorophenyl) - N - [3- methoxy-4- (4-methyl-5- Azyl)phenyl]-1,6-dimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine, 2-(2-chlorophenyl)-1,6-dimethyl - N -[6-(4-methyl-5- Oxadiazol-yl) -3-pyridinyl] -1 H - imidazo [4,5- c] pyridin-4-amine, 6-chloro-2- (5-fluoro-2-methylphenyl) - N - [ 6-(5-methyl-4- Azyl)-3-pyridyl]-imidazo[1,2- b ]嗒 -8-amine, 1-[8-[[3-methoxy-4-(4-methyl-5-) Azyl)phenyl]amino]-2-(2-methylpropyl)imidazo[1,2- a ]pyridin-6-yl]-ethanone, 2-(4-fluorophenyl)-3 - (2-methoxyethyl) - N - [3- methoxy-4- (2-methyl-5- Thiazolyl) phenyl] - and imidazo [1,2- a] pyridin-8-amine, 2- (4-fluorophenyl) - N - [4- [2- (methoxymethyl) -5- Azyl]phenyl]-1-(1-methylethyl)-1 H -benzimidazol-4-amine, 2-(2-chlorophenyl)-3-methyl- N- [6-( 2-methyl-5- Azyl)-3-pyridyl]-imidazo[1,2- a ]pyridine-8-amine, 2-methyl- N- [6-(2-methyl-5- Azyl)-3-pyridyl]-imidazo[1,2- a ]pyridine-8-amine, 2-(4-fluorophenyl)-3-methyl-5-(1-methylethyl) - N -[6-(2-methyl-5- Azyl)-3-pyridyl]-3 H -imidazo[4,5- b ]pyridine-7-amine, 2-(4-fluorophenyl)-3-methoxy- N- [6-( 4-methyl-5- Thiazolyl) -3-pyridinyl] - and imidazo [1,2- a] pyridin-8-amine, 2- (5-fluoro-2-methylphenyl) - N - [6- (4- Methyl -5- Azyl)-3-pyridyl]-imidazo[1,2- b ]嗒 8-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (1-methyl-1,2,3-triazol-4-yl H -1) phenyl ] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2-methyl -2 H -1, 2,3-triazol-4-yl) phenyl] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy - 4- (2-methyl-4-pyridinyl) phenyl] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy 4-(2-methyl-4-pyridyl)phenyl]-1,6-dimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine, 2-(4- Fluorophenyl)-1-methyl- N- [4-(2-methyl-4-pyridyl)phenyl]-1 H -benzimidazole-4-amine, 2-(2-chlorophenyl) - N- [3-methoxy-4-(2-methyl-4-pyridyl)phenyl]-3-methyl-imidazo[1,2-α]pyridine-8-amine, 2-( 4-fluorophenyl) - N - [3- methoxy-4- (2-methyl-4-pyridyl) phenyl] -1- (1-methylethyl) -1 H - benzimidazol- 4-amine, 2-(4-fluorophenyl)-1,6-dimethyl- N- [4-(2-methyl-4-pyridyl)phenyl]-1 H -imidazo[4 , 5- c] pyridin-4-amine, 2- (4-fluorophenyl) -1- (1-methylethyl) - N - [4- (2- methyl-4-pyridyl) phenyl ]-1 H -benzimidazole-4-amine, 2-(2-chlorophenyl)-3-methyl- N- [4-(2-methyl-4) - pyridinyl) phenyl] - and imidazo [1,2-α] pyridin-8-amine, 2- (4-fluorophenyl) - N - (2- methoxy-2'-methyl [3, 4'-bipyridine] -6-yl) -1- (1-methylethyl) -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - (2- methyl Oxy-2'-methyl[3,4'-bipyridine]-6-yl)-1-methyl-1 H -benzimidazole-4-amine, 2-(2-chlorophenyl) -N -(2-methoxy-2'-methyl[3,4'-bipyridine]-6-yl)-3-methyl-imidazo[1,2-α]pyridine-8-amine, 2- (4-fluorophenyl) - N - [6- methoxy-5- (1-methyl -1 H - pyrazol-4-yl) -2-pyridinyl] -1- (1-methylethyl yl) -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [6- methoxy-5- (1-methyl -1 H - pyrazol-4-yl )-2-pyridyl]-1-methyl-1 H -benzimidazol-4-amine, N- [4-(2,6-dimethyl-4-pyridyl)phenyl]-2-( 4-fluorophenyl)-1-(1-methylethyl)-1 H -benzimidazole-4-amine, N- [3-fluoro-4-(2-methyl-4-pyridyl)benzene 2-(4-fluorophenyl)-1-methyl-1 H -benzimidazole-4-amine, N- [3-fluoro-4-(2-methyl-4-pyridyl)benzene yl] -2- (4-fluorophenyl) -1- (1-methylethyl) -1 H - benzimidazol-4-amine, 2- (2-chlorophenyl) - N - [3- Fluoro-4-(2-methyl-4-pyridyl)phenyl]-3-methyl-imidazo[1,2- a ]pyridine-8- Amine, N- [3-fluoro-4-(2-methyl-4-pyridyl)phenyl]-2-(4-fluorophenyl)-1,6-dimethyl-1 H -imidazo[ 4,5- c ]pyridin-4-amine, 2-(4-fluorophenyl)-1-methyl- N- [6-(2-methyl-4-acridinyl)-3-indole -1 H -benzimidazol-4-amine, 2-(4-fluorophenyl)-1,6-dimethyl- N- [6-(2-methyl-4-pyridinyl)-3 -despair -1 H -imidazo[4,5- c ]pyridin-4-amine, and 2-(4-fluorophenyl)-1-methyl- N- [4-(4-pyridyl)phenyl ]-1 H -benzimidazole-4-amine, including any stereochemically isomeric form thereof, and pharmaceutically acceptable addition salts and solvates thereof.

In a particular embodiment, the compound of formula (I) preferably is 2- (4-fluorophenyl) - N - [3- methoxy-4- (4-methyl-5- Azolyl)phenyl]-1-methyl-1 H -benzimidazole-4-amine, including any stereochemically isomeric form thereof, and pharmaceutically acceptable addition salts and solvates thereof.

In a particular embodiment, the compound of formula (I) preferably is 2- (4-fluorophenyl) - N - [3- methoxy-4- (2-methyl-5- Azolyl)phenyl]-1-methyl-1 H -benzimidazole-4-amine, including any stereochemically isomeric form thereof, and pharmaceutically acceptable addition salts and solvates thereof.

In a particular embodiment, the compound of formula (I) preferably is 2- (4-fluorophenyl) -1- (1-methylethyl) - N - [6- (2- methyl-5 - Azolyl)-3-pyridyl]-1 H -benzimidazol-4-amine, including any stereochemically isomeric form thereof, and pharmaceutically acceptable addition salts and solvates thereof.

In a particular embodiment, the compound of formula (I) preferably is 2- (4-fluorophenyl) -1- (1-methylethyl) - N - [6- (2- methyl-5 - Azyl)-3-pyridyl]-1 H -benzimidazole-4-amine.

In one embodiment, Formula (I) compound is chosen from the group consisting of: 2- (4-fluorophenyl) -1- (1-methylethyl) - N - [6- (2 -methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 6-fluoro- N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-(2-methylpropyl)-imidazo[1,2- a ]pyridine-8-amine HCl, 2-(4-fluorophenyl)-6-methoxy- N -[3-methoxy-4-(2-methyl-5- Thiazolyl) phenyl] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (4-methyl - 5- Thiazolyl) phenyl] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2-methyl - 4-pyridyl)phenyl]-1-(1-methylethyl)-1 H -benzimidazole-4-amine, including any stereochemically isomeric form thereof, and pharmaceutically acceptable addition salts thereof And solvates.

In the preceding paragraph, features of specific embodiments may be combined with features of other specific embodiments or combinations of specific embodiments.

The invention also encompasses a process for the preparation of a compound of formula (I) and subgroups thereof, in which a reactive functional group, such as a hydroxyl group, an amine group, or a carboxyl group, which is required for the final product, may be protected to avoid Unnecessary participation in the reaction. Conventional protecting groups can be used in accordance with standard procedures, for example, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1999.

The compounds of formula (I) and subgroups thereof can be prepared in a sequential manner as described below, which is typically prepared from starting materials which are commercially available or prepared according to standard procedures which are not apparent to those skilled in the art. The compounds of the invention may also be prepared using standard synthetic methods commonly employed by those skilled in the art of organic chemistry.

Some common examples of preparation are as follows:

Experimental procedure 1

In general, the compounds of formula (I) can be prepared starting from Scheme 1 below, wherein all variables are as defined above:

The compound of formula (I) can be prepared via a coupling reaction between intermediates of formula (II-a) and (III-a) or intermediates of formula (II-b) and (III-b) wherein halogen is defined as Cl , Br or I, and all other variables therein are as defined above. This reaction can be carried out in the presence of a suitable base such as Cs2CO3 or sodium butoxide. The reaction can be carried out in a reaction inert solvent such as toluene, N , N -dimethylformamide (DMF), tert-butanol or two alkyl. The reaction can generally be carried out in the presence of a catalyst system comprising a suitable catalyst such as palladium(II) acetate (Pd(OAc) ₂ ) or bis(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ) and a ligand such as (9,9-dimethyl-9 H -dibenzopyran-4,5-diyl)bis[diphenylphosphine] (Xantphos), [1,1'-bisnaphthalene] -2,2'-diylbis[diphenylphosphine](BINAP), or dicyclohexyl[2',4',6'-parade(1-methylethyl)[1,1'-diphenyl Alkyl-2-yl]-phosphine (X-phos). Preferably, the reaction is carried out under inert gas pressure, such as nitrogen or argon pressure. The reaction rate and yield can be enhanced by microwave-assisted heating.

In another manufacturing process, this is only valid when different Het ² in Y ^1, Y ^3, Z ¹ or Z ³ is N, which Y ^1, Y ^3, Z ¹ or Z ³ is N of the formula (I) The compound can be prepared by aromatic nucleophilic substitution of the intermediates of the formulae (II-a) and (III-a), and the reaction can be carried out in the presence of a suitable base such as K ₂ CO ₃ or diisopropyl B. Amine. The reaction can be carried out in a reaction inert solvent such as DMF or CH ₃ CN. This reaction can also be carried out under acidic conditions, for example in the presence of HCl or methanesulfonic acid. This reaction can be carried out in a reaction inert solvent such as 2-propanol. The reaction rate and yield can be enhanced by microwave-assisted heating.

Experimental procedure 2

The compound of formula (I) can also be prepared according to Scheme 2 by a coupling reaction between an intermediate of formula (IV) and an intermediate of formula (V) wherein halo is defined as Cl, Br or I, and wherein all other variables are as previously described definition.

In Scheme 2, the intermediate of formula (V) can be prepared commercially or can be prepared according to conventional reaction procedures generally known in the art. The coupling reaction is carried out in the presence of a suitable base such as Cs ₂ CO ₃ , Na ₂ CO ₃ or NaOH. The reaction can be carried out in a reaction inert solvent such as, for example, toluene, DMF or alkyl. The reaction is usually carried out in the presence of a catalyst such as ruthenium (triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ). Stirring, elevated temperatures (e.g., between 70-140 ° C) and/or pressure may enhance the rate of the reaction. Preferably, the reaction is carried out under inert gas pressure, such as nitrogen or argon.

Alternatively, the boronic acid pinacol ester derivative of formula (V) can be replaced by the corresponding boronic acid derivative.

Experimental procedure 3

Alternatively, a compound of formula (I) can also be prepared according to Scheme 3 via a coupling reaction between an intermediate of formula (VI) and an intermediate of formula (VII) wherein halo is defined as Cl, Br or I, and all other The variables are as defined above.

Flow chart 3

In Scheme 3, the intermediate of formula (VII) can be prepared commercially or can be prepared according to conventional reaction procedures generally known in the art. The reaction conditions were similar to those described in Experimental Procedure 2.

Experimental procedure 4

The intermediate of formula (II-a) can be prepared via reduction of the intermediate of formula (VIII) as shown in Scheme 4, wherein all variables are as defined above.

Reduction of (VIII) to (II-a) can be carried out by a conventional method such as reduction hydrogenation or by metal or metal salt and acid [for example, a metal such as iron, or a metal salt such as SnC1 ₂ , and an acid such as a mineral acid (hydrogen) Reduction of chloric acid, sulfuric acid, etc. or organic acids (acetic acid, etc.), or other well-known methods of converting the nitro group to the corresponding amine.

Experimental procedure 5

Its Het ^{1 is} defined as being substituted by R ⁰ at the 4-position. The intermediate of formula (VIII) of azole 4 is therefore referred to as the intermediate of formula (XI) and can be prepared by condensation of an intermediate of formula (X) with an intermediate of formula (IX) as shown in Scheme 5. The intermediate product (IX) can be commercially available or can be prepared according to conventional reaction procedures generally known in the art. This condensation reaction is carried out in the presence of a suitable base such as K ₂ CO ₃ or sodium ethoxide (NaOEt). The reaction can be carried out in a protic solvent such as methanol (MeOH) or ethanol (EtOH). Stirring and/or high temperatures (eg, between 70-110 ° C) enhance the reaction rate. In flowchart 5, all variables are as defined above.

Alternatively, the reaction described in Scheme 5 can also be carried out with a benzaldehyde derivative of the intermediate of formula (IX) wherein NO _{2 is} replaced by Cl, Br, I, or NH-Het ² .

Experimental procedure 6

According to Scheme 6, the intermediate product of formula (II-a) can also be prepared by converting the halogen substituent of the intermediate of formula (II-b) to an amine group using reaction conditions well known in the art, or masking or protecting it can be followed by Amino functionality that is converted to an amine group. In Scheme 6, halogen is defined as Cl, Br or I, and all other variables are as defined above.

An intermediate of formula (II-b) wherein Het ^{1 is} defined as substituted by R ⁰ The azole, thus referred to as the intermediate of formula (XII-b), can be prepared starting from the intermediate of formula (XII) according to the synthetic procedure used to synthesize intermediate (XI):

The intermediate of formula (XII) is commercially available or can be prepared according to conventional reaction procedures generally known in the art.

Experimental procedure 7

An intermediate of formula (VIII) wherein Het ^{1 is} defined as being substituted at the 2-position with R ¹ and at the 4-position with CH ₃ The azole, thus referred to as the intermediate of formula (XIII), can be prepared according to Scheme 7 via a condensation reaction of an intermediate of formula (XIV) with an intermediate of formula (IX) wherein all other variables are as defined above. The two intermediates may be commercially available or may be prepared according to conventional reaction procedures generally known in the art, and the condensation reaction is usually carried out in a solvent such as pyridine. Stirring and/or high temperatures (eg, between 70-110 ° C) enhance the reaction rate.

Experimental procedure 8

The intermediate of formula (IV) can be prepared by a coupling reaction between an intermediate of formula (XV) and an intermediate of formula (III-a), as shown in Scheme 8, wherein halogen is defined as Cl, Br or I, and all other The variables are as defined above. This reaction can be carried out analogously to the synthetic procedure described in Experimental Procedure 1.

Experimental procedure 9

An intermediate of formula (VIII), wherein Het ^{1 is} defined as shown in Scheme 9, and is therefore referred to as an intermediate of formula (XVIII), can be prepared by condensation of an intermediate of formula (XVII) with an intermediate of formula (XVI), It is activated as iodobenzene diacetate in the presence of trifluoromethanesulfonic acid. Stirring and / or high temperature (eg 70-100 ° C) can increase the reaction rate. In Scheme 9, R ^{1a is} defined as C _1-4 alkyl, and all other variables are as defined above.

Wherein the intermediate product is NO ₂ or Cl Br displacement of formula (XVIII) can be prepared therefrom corresponding halo intermediate ₂ (each Cl or Br) displacement of formula (XVI) NO.

Experimental procedure 10

The intermediate of formula (VIII), which Het ^{1 is} defined as shown in Scheme 10, is thus referred to as the intermediate of formula (XXI) and can be passed via condensation of (XIX) intermediates with formula (XX) as shown in Scheme 10. Intermediate product preparation in which all variables are as defined above. Usually the reaction can be carried out in acetic acid, and the reaction rate can be enhanced by stirring and/or high temperature (up to 90 ° C).

Experimental procedure 11

The intermediate of formula (XIX) can be prepared via condensation of dimethylformamide dimethyl acetal (DMF-DMA) with an intermediate of formula (XVI) as described in Scheme 11. Stirring and / or high temperature (for example between 70-110 ° C) can enhance the reaction rate.

Experimental procedure 12

An intermediate of formula (III-a) wherein Het ^{2 is} defined to produce an intermediate of formula (XXIV) can be prepared by condensation of an intermediate of formula (XXII) with an intermediate of formula (XXIII) as illustrated in Scheme 12. Wherein halogen is defined as Br and Cl, and all other variables therein are as defined above. The reaction can be carried out in a reaction-inert solvent such as EtOH or n-butanol, or via mixing of a solvent-free reagent. The reaction can be conveniently carried out at a high temperature between 50 ° C and the reflux temperature of the reaction mixture. The reaction rate and yield can be enhanced by microwave-assisted heating.

Experimental procedure 13

An intermediate of formula (III-a) wherein Het ^{2 is} defined to produce an intermediate of formula (XXVII) wherein R ^6b is attached to the benzimidazole heterocycle via carbon can be via formula (XXV) intermediates and formulas according to Scheme 13 The (XXVI) intermediate product is subjected to a deuteration reaction, followed by a condensation reaction to give (XXVII), wherein the halogen is defined as Br, Cl and I, and wherein all other substituents are as defined above. The deuteration reaction can be carried out in a solvent such as pyridine or a reaction inert solvent such as DMF in the presence of a base such as triethylamine (Et ₃ N). The subsequent condensation reaction can be carried out by heating the crude deuterated product in a solvent such as acetic acid.

Experimental procedure 14

Alternatively, an intermediate of formula (XXVII) wherein R ^6b is attached to the benzimidazole heterocycle via a carbon can also be prepared by treating the intermediate (XXV) with an aldehyde of formula (XXVIII). The reaction can be carried out according to Scheme 14, in the presence of sodium metabisulfite in a reaction inert solvent such as N , N -dimethylacetamide (DMA), wherein the halogen is defined as Br, Cl and I, and all others Substituents are as defined above.

Experimental procedure 15

Alternatively, an intermediate of formula (XXVII) wherein R ^6b is attached to the benzimidazole heterocycle via a carbon can also be prepared by treating the intermediate (XXIX) with an aldehyde of formula (XXVIII). The reaction can be carried out according to Scheme 15 in the presence of sodium disulfate in a reaction inert solvent such as EtOH wherein the halogen is defined as Br, Cl and I, and wherein all other substituents are as defined above.

With respect to the intermediate of formula (XXVII) wherein R ⁷ is H, another R ⁷ may be introduced via N -alkylation, primarily to form an intermediate of formula (XXVII) wherein R ⁷ is a substituent as defined above in addition to hydrogen. .

Experimental procedure 16

The intermediate of formula (XXV) can be prepared via reduction of the intermediate (XXIX) as shown in Scheme 16, wherein the halogen is defined as Br, Cl, and I, and wherein all other substituents are as defined above. Reduction of (XXIX) to (XXV) can be carried out by conventional methods, such as reductive hydrogenation, or as a metal or a metal salt and an acid [eg a metal such as iron, or a metal salt such as SnCl ₂ , and an acid such as a mineral acid ( Reduction of hydrochloric acid, sulfuric acid, etc. or organic acids (acetic acid, etc.), or other well known methods for converting a nitro group to a corresponding amine.

Experimental procedure 17

The intermediate of formula (XXIX) can be prepared as shown in Scheme 17, by substituting the intermediate of formula (XLV) for the intermediate of formula (XXX) wherein halogen is defined as Br, Cl and I, and halogen-b is defined as F, Cl or Br, and all other substituents therein are as defined above. Formula (XLV) intermediates are either commercially available or can be prepared according to conventional reaction procedures generally known in the art.

Experimental procedure 18

The intermediate of formula (VIII) can be prepared via a coupling reaction of an intermediate of formula (XXXI-a) with (XXXII-a) or an intermediate of formula (XXXI-b) with (XXXII-b), which is shown in Scheme 18 Wherein halogen is defined as Br, Cl and I, and all other variables therein are as defined above. In Scheme 18, the intermediates of formula (XXXI-a), (XXXI-b), (XXXII-a), and (XXXII-b) can be prepared commercially or can be prepared according to conventional reaction procedures generally known in the art. The coupling reaction is carried out in the presence of a suitable base such as CS ₂ CO ₃ , Na ₂ CO ₃ or NaOH. The reaction can be carried out in a reaction inert solvent such as toluene, DMF or tetrahydrofuran (THF). The reaction is usually carried out in the presence of a catalyst system containing a suitable catalyst such as palladium(II) acetate (Pd(OAc) ₂ ) and a ligand such as triphenylphosphine. Stirring, high temperatures (eg, between 70-140 ° C) and/or pressure enhance the reaction rate. This reaction is preferably carried out under inert gas pressure, such as nitrogen or argon pressure. Instead of boric acid (XXXII-a) or (XXXI-b), a corresponding borate ester such as pinacol ester can be used.

Experimental procedure 19

The intermediate of formula (XVI) can be prepared according to Scheme 19 by coupling of an intermediate of formula (XXXI-a) with tributyl(1-ethoxyvinyl)tin, wherein halogen is defined as Br, Cl or I, And all other variables therein are as defined above. In Scheme 19, the intermediate of formula (XXXI-a) can be prepared commercially or can be prepared according to conventional reaction procedures generally known in the art. The reaction can be carried out in a reaction inert solvent such as toluene or DMF. The reaction is usually carried out in the presence of a catalyst such as Pd(PPh ₃ ) ₄ . Stirring, high temperatures (eg, between 70-140 ° C) and/or pressure enhance the reaction rate. This reaction is preferably carried out under inert gas pressure, such as nitrogen or argon pressure. Subsequently, the obtained ethanol can be hydrolyzed under acidic conditions, for example using hydrochloric acid, to produce an acetamidine derivative of the formula (XVI).

Experimental procedure 20

The intermediate of formula (XXXV) can be prepared by condensation of an intermediate of formula (XXXIV) with an intermediate of formula (XXXIII) as shown in Scheme 20, wherein R ^{1a is} defined as C _1-4 alkyl, and all other Substituents are as defined above. The reaction can be carried out in a solvent such as pyridine. Stirring, high temperature (for example between 70 and 100 ° C) can enhance the reaction rate.

Experimental procedure 21

The intermediate of formula (XXXIV) can be prepared via an activation reaction of an intermediate of formula (XXXVI) as shown in Scheme 21, wherein all variables are as defined above. The reaction can be carried out in the presence of DMF in a reaction inert solvent such as chloroform. The reaction is usually carried out in the presence of an active agent such as SOCl ₂ . Stirring, high temperature (for example between 50 and 80 ° C) can enhance the reaction rate.

Experimental procedure 22

The intermediate of formula (XXXIX) can be prepared according to Scheme 22, via a coupling reaction of an intermediate of formula (XXXVII) with an intermediate of formula (XXXVIII) wherein halogen is defined as I or Br, and wherein all other variables are as defined above. In Scheme 22, the intermediates of formula (XXXVII) and (XXXVIII) may be commercially available or may be prepared according to conventional reaction procedures generally known in the art. The coupling reaction is carried out in the presence of a suitable base, such as Cs ₂ CO ₃ , or Ag ₂ CO ₃ . The reaction can be carried out in a reaction inert solvent such as H ₂ O, CH ₃ CN or DMF. The reaction is usually carried out with a suitable catalyst (for example, palladium(II) acetate (Pd(OAc) ₂ ) or 1.1-bis(diphenylphosphinoferrocene dichloropalladium II) (Pd(dppf)Cl ₂ )) and a ligand. The catalyst system (for example triphenylphosphine) is carried out in the presence of a catalyst system. Stirring, high temperature (for example between 60 and 140 ° C) can enhance the reaction rate.

Experimental procedure 23

The intermediate of formula (XLI) can be prepared via the decarboxylation of a compound of formula (XL) as described in Scheme 23, wherein the halogen is defined as Br, I or Cl, and wherein all other variables are as defined above. The reaction can be carried out in the presence of copper (II) oxide (CuO) in a solvent such as quinoline or DMF. The reaction usually requires high temperatures (up to 150 ° C).

Experimental procedure 24

The intermediate of formula (XL) can be prepared by hydrolysis of a carboxylic acid ester of a compound of formula (XLII) as described in Scheme 24, wherein halogen is defined as Br, I or Cl, and wherein all other variables are as defined above. This reaction can be carried out under acidic conditions or under basic conditions, preferably in two The mixture of alkane and water is carried out under basic conditions at room temperature in the presence of a base, such as NaOH or LiOH.

Experimental procedure 25

The intermediate of formula (XLII) can be prepared by a coupling reaction of an intermediate of formula (XLIII) with an intermediate of formula (XLIV) as described in Scheme 25, wherein halogen is defined as Br, I or Cl, wherein halogen-c is defined as Br Or I, and all other variables therein are as defined above. The intermediates of formula (XLIII) and formula (XLIV) can be prepared commercially or can be prepared according to conventional reaction procedures generally known in the art. The coupling reaction is carried out in the presence of a suitable base, such as Cs ₂ CO ₃ or Ag ₂ CO ₃ . The reaction can be carried out in a reaction inert solvent such as CH ₃ CN, toluene or DMF. The reaction is usually carried out with a suitable catalyst (for example palladium(II) acetate (Pd(OAc) ₂ ) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl ₂ )) and the presence of a ligand (for example triphenylphosphine or tri-o-tolylmethylphosphonium) catalyst system in the presence of a catalyst system. Stirring, high temperature (for example between 60 and 140 ° C) can enhance the reaction rate.

Any one or more of the following further steps may be performed in any order, as needed or desired:

The compounds of formula (I), any subgroups thereof, addition salts, solvates, and stereochemically isomeric forms can be converted to other compounds of the invention using procedures known in the art. In certain instances, a compound of formula (I) wherein R ^4a or R ^{4b is} defined as Cl, Br or I may be further derivatized such that R ^4a or R ^4b is H, under reducing conditions well known to those skilled in the art. a compound of formula (I).

It will be appreciated by those skilled in the art that in the above procedures, the functional groups of the intermediate compound need to be blocked with a protecting group. In the case where the functional group of the intermediate compound is blocked by a protecting group, it can be deprotected after the reaction step.

Pharmacology

The compounds of the invention have been found to modulate γ-secretase activity, and thus the compounds of the invention and their pharmaceutically acceptable compositions are useful for the treatment or prevention of Alzheimer's disease (AD), traumatic brain injury, mild cognitive impairment (MCI), Aging, dementia, Lewy body dementia, cerebral amyloid angiopathy, multiple infarct dementia, Down's syndrome, Parkinson's disease-related dementia, and β-amyloid-related dementia, preferably used Alzheimer's disease.

As used herein, the term "modulating γ-secretase activity" means effective treatment of APP with a γ-secretase-complex, which preferably means that the effect is the overall proportion of APP treatment when the compound is not administered. Substantially the same, but the relative amount of the treated product changes, and more preferably, the amount of A?42-peptide produced is reduced in this manner. For example, different Aβ species (eg, Aβ-38 or other shorter amino acid sequence Aβ peptide species can be substituted for Aβ-42) or the relative amounts of products are different (eg, the ratio of Aβ-40 to Aβ-42 is changed, Good place to increase).

It has previously been shown that the γ-secretase complex is also involved in the treatment of Notch-protein, a signaling protein that plays an important role in the development process (see, for example, Schweisguth F (2004) Curr. Biol. 14, R129). Regarding the therapeutic use of gamma-secretase modulators, in order to avoid hypothetical undesired side effects, it appears to be particularly advantageous for Notch-treatment activity that does not interfere with gamma-secretase activity. At the same time, γ-secretase inhibitors show that γ-secretase modulators have the advantage of selectively reducing the high aggregation and neurotoxic form of Aβ (ie, Aβ42) due to the side effects associated with inhibition of Notch treatment, without reducing the production. Aβ, which is less aggregated (ie, Aβ38), is not accompanied by inhibition of Notch treatment. Therefore, the compound preferably does not exhibit an effect on the Notch-treatment activity of the γ-secretase-complex.

As used herein, the term "therapeutic" is intended to mean all processes that slow, interrupt, arrest, or stop the progression of a disease, but does not necessarily represent a complete exclusion of all symptoms.

The present invention relates to a compound of the formula (I), a stereoisomeric form thereof, and pharmaceutically acceptable acid or base addition salts and solvates thereof.

The invention also relates to a compound of the formula (I), a stereoisomeric form thereof, and pharmaceutically acceptable acid or base addition salts and solvates thereof for use in the treatment or prevention of a disease or selected from the group consisting of Alzheimer's disease ( AD), traumatic brain injury, mild cognitive impairment (MCI), aging, dementia, Lewy body dementia, cerebral amyloid angiopathy, multiple infarct dementia, or Down's syndrome.

In a specific embodiment, the disease or condition is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, aging, dementia, Lewy body dementia, cerebral amyloid angiopathy, multiple infarct dementia, or Tang Disease.

In a specific embodiment, the disease or condition is preferably Alzheimer's disease.

The invention also relates to a compound of formula (I), a stereoisomeric form thereof, and pharmaceutically acceptable acid or base addition salts and solvates thereof for use in the treatment of the disease.

The invention also relates to a compound of the formula (I), a stereoisomeric form thereof and pharmaceutically acceptable acid or base addition salts and solvates thereof for use in the treatment or prophylaxis, in particular in the treatment of γ-secretase Disease or symptom.

The invention also relates to a compound of formula (I), a stereoisomeric form thereof, and pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the manufacture of a medicament.

The invention also relates to a compound of formula (I), a stereoisomeric form thereof, and pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the manufacture of a medicament for modulating gamma-secretase activity.

The invention also relates to a compound of formula (I), a stereoisomeric form thereof, and pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the manufacture of a medicament for the treatment or prevention of any of the aforementioned conditions of the disease.

The invention also relates to a compound of formula (I), a stereoisomeric form thereof, and pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the manufacture of a medicament for the treatment of any of the aforementioned conditions.

In the present invention, a compound of the formula (I) having an IC ₅₀ value which inhibits the production of Aβ42-peptide is less than 1000 nM, or any of its members, is preferably provided when assayed by appropriate analysis, for example, for the following analysis. The population, preferably less than 100 nM, more preferably less than 50 nM, and even less preferably less than 20 nM.

The compounds of the invention may be administered to a mammal, preferably a human, to treat or prevent any of the foregoing diseases.

In view of the utility of the compound of formula (I), there is provided a method of treating a warm-blooded animal (including a human) suffering from any of the aforementioned diseases, or a method of preventing any of the aforementioned diseases in a warm-blooded animal, including a human.

The method comprises administering, i.e., systemically or topically, preferably orally, an effective amount of a compound of formula (I), a stereoisomeric form thereof, and a pharmaceutically acceptable addition salt or solvate thereof to the temperature. Blood animals, including humans.

Those who are familiar with the treatment of such diseases can determine the effective daily therapeutic amount from the test results described later. The effective daily therapeutic amount can be from about 0.005 mg/kg to 50 mg/kg, especially from 0.01 mg/kg to 50 mg/kg. More particularly, from 0.01 mg/kg body weight to 25 mg/kg body weight, preferably from about 0.01 mg/kg body weight to about 15 mg/kg body weight, more preferably from about 0.01 mg/kg body weight to about 10 mg/kg body weight. More preferably, it is from about 0.01 mg/kg body weight to about 1 mg/kg body weight, optimally from about 0.05 mg/kg body weight to about 1 mg/kg body weight. The amount of the compound of the present invention as used herein also refers to the active ingredient which is of course required to achieve a therapeutic effect, depending on the condition, for example, the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease to be treated. .

The method of treatment may also include administering the active ingredient in a regimen of one to four intakes per day. In these methods of treatment, the compounds of the invention are preferably formulated prior to administration. Suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients, as described below.

The compounds of the invention suitable for treating or preventing Alzheimer's disease or a symptom thereof may be administered alone or in combination with one or more other therapeutic agents. Combination therapy comprises administering a separate pharmaceutical formulation comprising a compound of formula (I) and one or more additional therapeutic agents, and administering a compound of formula (I) and each of the other therapeutic agents, eg, I) The compound and the therapeutic agent can be administered to a patient together in a single oral dosage composition such as a lozenge or capsule, or each agent can be administered in a separate pharmaceutical formulation.

When the active ingredient can be administered alone, it is preferably present as a pharmaceutical composition.

Accordingly, the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) as an active ingredient.

The carrier or diluent must be "acceptable" and conceptually compatible with the other ingredients of the composition and not deleterious to the recipient.

With respect to ease of administration, the subject compounds can be formulated into different pharmaceutical forms for administration purposes, especially the compounds of formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemically isomeric forms thereof, Or any subgroup or combination thereof, can be adapted to form a different form of medicine for the purpose of administration. When a suitable composition is exemplified, all of the compositions are generally used for systemic administration of the agent.

In order to prepare the pharmaceutical composition of the present invention, an effective amount of a specific compound (optionally in the form of an addition salt) as an active ingredient is intimately mixed with a pharmaceutically acceptable carrier, and the carrier may be variously formulated according to the form of the preparation to be administered. Ingestion, these pharmaceutical compositions are satisfactorily suitable, in particular, in a single dosage form for oral administration, rectal administration, transdermal administration, parenteral injection or inhalation, for example in the preparation of oral dosage compositions Any conventional pharmaceutical medium such as water, glycols, oils, alcohols, etc., in the case of oral liquid preparations, such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starch , sugar, kaolin, thinner, lubricant, binder, disintegrant, etc., in the case of powders, pills, capsules and lozenges. Because lozenges and capsules are easy to administer, they represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. With regard to parenteral compositions, the carrier typically comprises sterile water, which may comprise at least a majority, although other ingredients, such as a solubilizing agent, may be included. The injection solution can be prepared, for example, by using an aqueous salt solution, a glucose solution or an injection solution of a mixture of saline and a glucose solution. For example, the carrier can be prepared by including an aqueous solution of saline, a glucose solution or an injection solution of a mixture of saline and glucose solution. . An injection solution comprising a compound of formula (I) may be formulated in an oil for prolonged action, and suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerides of long-chain fatty acids and Mixtures with other oils. The injectable suspension may also be prepared using a suitable liquid carrier, suspension, or the like, as well as solid form preparations which are intended to be converted into liquid form preparations immediately before use. In a composition suitable for transdermal administration, the carrier optionally comprises an osmotic booster and/or a suitable humectant, optionally incorporating suitable additives of any nature in minor proportions which do not cause significant on the skin. Bad effects. The additive can facilitate administration to the skin and/or can aid in the preparation of the desired composition. These compositions can be administered in a variety of ways, for example, through skin infiltrated patches, drops, ointments. The acid or base addition salts of the compounds of formula (I) are more suitable for the preparation of aqueous compositions because of the increased water solubility beyond the corresponding base or acid form.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions into unit dosage forms which are easy to administer and homogeneous in dosage. The unit dosage form as used herein refers to physically discrete units suitable as a single dosage unit, each unit containing a predetermined quantity of the active ingredient which produces the desired therapeutic effect, and incorporating the desired pharmaceutical carrier. Examples of such unit dosage forms are lozenges (including truncate or film-coated tablets), capsules, pills, powder packets, tablets, suppositories, injection solutions or suspensions, and the like, and the multi-unit form thereof.

Since the compound of the present invention is an effective oral compound, it is particularly advantageous to use an oral pharmaceutical composition comprising the compound.

In order to enhance the solubility and/or stability of the compound of formula (I) in a pharmaceutical composition, it is advantageous to use α-, β- or γ-cyclodextrin or a derivative thereof, in particular a hydroxyalkyl-substituted cyclodextrin, For example 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Further, a cosolvent such as an alcohol enhances the solubility and/or stability of the compound of the present invention in a pharmaceutical composition.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, more preferably from 0.1 to 50% by weight, of the compound of formula (I), and from 1 to 99.95 by weight. More preferably, it is from 30 to 99.9% by weight, more preferably from 50 to 99.9% by weight of the pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The following examples illustrate the invention.

Example

Hereinafter, the term "DCM" means dichloromethane; "MeOH" means methanol; "LCMS" means liquid chromatography/mass spectrometry; "aq." means aqueous; "sat." means saturated; "sol." means solution; "HPLC" means high performance liquid chromatography; "rt" means room temperature; "AcOH" means acetic acid; "mp" means melting point; "Et ₂ O" means diethyl ether; "BDS" means alkali deactivated cerium oxide; RP" means reverse phase; "min" means minute (s); "h" means hour (s); "ID" means inner diameter; "Pd(OAc) ₂ " represents palladium acetate (II); "LiHMDS" means six Lithium methyl diazoxide; "HBTU" means 1-[bis(dimethylamino)methylene]-1H-benzotriazol-1-indole-3-oxide hexafluorophosphate; "Xantphos" Represents (9,9-dimethyl-9H-dibenzopyran-4,5-diyl) bis[diphenylphosphine]; "X-Phos" means dicyclohexyl [2', 4', 6 '-Tris(1-methylethyl)[1,1'-bisphenyl]-2-yl]-phosphine;"NH ₄ OAc" means ammonium acetate; "NMP" means 1-methyl-2-pyrrole piperidinone; "SFC" denotes supercritical fluid chromatography; "iPrNH _2" represents diisopropylamine; "DME" represents 1,2- Ethane; "EtOAc" for ethyl acetate; "BINAP" represents a [1,1'-bis-naphthalene] -2,2'-diyl-bis [diphenylphosphino] (rac); "Et ₃ N" Represents triethylamine; "EtOH" means ethanol; "Pd(PPh ₃ ) ₄ represents hydrazine (triphenylphosphine) palladium; "PPh ₃ " represents triphenylphosphine; "eq" represents equivalent; "rm" represents reaction mixture "DIPE" means diisopropyl ether; "DIPEA" means diisopropylethylamine; "DMA" means N,N -dimethylacetamide; "THF" means tetrahydrofuran; "DMSO" means dimethylene DM; "DMF" means N, N -dimethylformamide; "DMF-DMA" means dimethylformamide dimethyl acetal; "PdCl ₂ (PPh ₃ ) ₂ means dichloro bis (three Phenylphosphine)palladium; "KOtBu" means potassium t-butoxide; "Ph(Ph ₃ ) ₄ " means palladium (triphenylphosphine) palladium and "Pd ₂ (dba) ₃ represents three [μ-[(1, 2-η: 4,5-η)-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one]]dipalladium.

A. Preparation of intermediate products Example A1 a) Preparation of intermediate product 1

K ₂ CO ₃ (9.6 g, 69.5 mmol) and 1-methyl-1-p-toluenesulfonylmethylisocyanide (8 g, 38.2 mmol) were added to the 2-carboyl group- A solution of 5-nitromethoxybenzene (6.29 g, 34.7 mmol) in MeOH (150 mL). phase was washed with H ₂ O, dried (MgSO _4), filtered and the solvent was evaporated in vacuo, and the residue was purified on a silica gel chromatography step (eluent to: n-heptane / EtOAc 100/0 to 50 / 50). The product fractions were collected and the solvent was evaporated. Yield: 6.24 g of intermediate 1 (77%).

b) Preparation of intermediate product 2

MeOH (150 ml) was added to Pd/C 10% (1 g) under N ₂ pressure, then a solution of 0.4% thiophene in DIPE (1 mL) and intermediate 1 (6.24 g, 26.6 mmol) were added. ). The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were} absorbed. The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. Yield: 5.4 g of intermediate 2 (99%).

Example A2 a) Preparation of intermediate product 3

Iodobenzene diacetate (5.49 g, 18.44 mmol) and trifluoromethanesulfonic acid (6.08 ml, 69.17 mmol) were stirred at room temperature under N ₂ in CH ₃ CN (100 mL) for 1 hour. . 2'-Methoxy-4'-nitro-acetophenone (3.0 g, 15.37 mmol) was added to the solution at room temperature, then the reaction mixture was refluxed for 2 h then cooled to room temperature and carefully added to stirred solution of saturated aqueous Na ₂ CO ₃ (500 mL). The product was extracted with DCM and the organic phase was dried (MgSO _4), filtered and the solvent evaporated under reduced pressure. The resulting dark brown oil was purified by flash column chromatography (eluent: DCM / MeOH. The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 3.0 g Intermediate 3 (75%).

b) Preparation of intermediate product 4

The MeOH (50 mL) was added to Pd / C 10% (0.250 g) under N ₂ pressure, followed by the addition containing DIPE 0.4% thiophene of (2 mL) and Intermediate 3 (0.946 g, 4.04 mmol). The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were taken} . The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. The product was triturated in DIPE, filtered and dried under vacuum. Yield: 0.66 g of intermediate 4 (80%).

Example A3 Preparation of intermediates 5

3-Bromo-2-pyridinamine (24.9 g, 144 mmol), 2-bromo-1-(3-methoxyphenyl)-1-propanone (42 g, 172.8 mmol) and 250 mL The n-butanol was heated at reflux temperature for 3 nights and the mixture was separated between DCM and water. The organic layer was dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel in _{(eluent: DCM / MeOH (NH 3)} 100/0 to 98/2). The most filtrate was concentrated under reduced pressure and the residue was crystallised from DIPE. Yield: 19 g of intermediate product 5 (42%).

Example A4 Preparation of intermediates 6

Add Cs ₂ CO ₃ (4.1) to a solution of intermediate 5 (2 g, 6.3 mmol) and 4-bromo-3-methoxyaniline (1.40 g, 6.93 mmol) in DMF (40 mL) g, 12.61 mmol, Pd ₂ (dba) ₃ (0.144 g, 0.158 mmol) and BINAP (0.196 g, 0.315 mmol), and the mixture was rinsed with N _{2 for} 5 min. The reaction mixture was heated at 120 °C for 2 hours and then cooled to room temperature. H ₂ O (300 ml) and EtOAc (300 mL) were evaporated. The organic phase was separated, washed with H ₂ O and brine, dried (MgSO _4), filtered and evaporated to dryness. The residue was crystallized from EtOH, filtered and dried. Yield: 1.8 g of intermediate 6 (65%).

Example A5 Preparation of intermediates 7

Bis (frequency sodium alcohol) diborane (0.191 g, 0.753 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (0.020 g, 0.025 mmol) and potassium acetate (0.049 g, 0.502 mmol) was added to a solution of intermediate 6 (0.110 g, 0.251 mmol) of DMF (10 mL) was added, and the mixture was flushed with N ₂ 10 minutes. The reaction mixture was heated at 120 ° C for 5 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated and evaporated. ₂ O was washed with brine and the organic phase H, dried (MgSO _4), filtered and evaporated to dryness. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc:EtOAc: Yield: 0.070 g of intermediate 7 (57%).

Example A6 a) Preparation of intermediate product 8

2-Methoxy-4-nitrobenzaldehyde (4.677 g, 25.817 mmol) and 2-acetamide acrylic acid (5 g, 38.725 mmol) were added to pyridine (50 mL) and the reaction mixture Stir at 120 ° C overnight. After cooling, the reaction mixture was poured into H ₂ O, and the product was extracted with EtOAc, the organic phase separated, dried (MgSO _4), filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc Yield: 0.9 g of intermediate 8 (14%).

b) Preparation of intermediate products 9

Under N ₂ pressure, and MeOH (50 mL) was added to Pd / C 10% (0.2 g), followed by the addition containing DIPE 0.4% thiophene of (0.5 ml) and Intermediate 8 (0.9 g, 3.62 mmol ). The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were taken} . The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. Yield: 5.4 g of intermediate 9 (88%).

Example A7 a) Preparation of intermediate product 10

DMF-DMA containing 2'-methoxy-4'-nitro-acetophenone (90564-14-0, 3.07 g, 15.73 mmol) was refluxed for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Yield: 3.63 g of intermediate 10 (92%).

b) Preparation of intermediates 11 and 12

The intermediate product 10 (3.63 g, 14.505 mmol) was added to a solution of methyl hydrazine (0.84 mL, 15.956 mmol) in AcOH (20 mL) and the mixture was stirred at 90 ° C for 3 hours. . The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on eluent (eluent: DCM / n-heptane 50/50 to 70/30). Yield: 1.44 g of intermediate 11 (42%) and 0.83 g of intermediate 12 (24%).

c) preparation of intermediate products 13

Under N ₂ pressure, the (50 mL) was added MeOH Pd / C 10% (0.2 g). Subsequently, a solution of 0.4% thiophene in DIPE (1 ml) and intermediate 12 (0.83 g, 3.57 mmol) were added. The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were taken} . The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. Yield: 0.72 g of intermediate 13 (98%).

Example A8 a) Preparation of intermediate product 14

First add K ₂ CO ₃ (14.84 g, 107.5 mmol), then add 1-methyl-1-p-toluenesulfonylmethylisocyanide (13.5 g, 64.5 mmol) to 6-bromopyridine A solution of 3-formaldehyde (10.0 g, 53.76 mmol) in 200 mL of MeOH. The reaction mixture was refluxed for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM, and the organic phase was washed with H ₂ O, dried (MgSO _4), filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on EtOAc EtOAc (EtOAc:EtOAc:EtOAc: The material was dried at 50 ° C under vacuum. Yield: 6.8 g of intermediate 14 (53%).

b) Preparation of intermediate products 15

2-methyl-2-propanol sodium salt (0.804 g, 8.36 mmol), BINAP (0.521 g, 0.837 mmol), Pd ₂ (dba) ₃ (0.383 g, 0.418 mmol) and Phenyl ketimine (0.948 g, 5.23 mmol) was added to a solution of intermediate 14 (1.0 g, 4.18 mmol) in toluene (20 mL). The reaction mixture was degassed and placed under N ₂ pressure. The reaction mixture was stirred in a microwave at 100 ° C for 2 hours. After cooling, most of the solvent was evaporated (almost dry) and 1N HCl: THF solution (1/1, 100 mL) was added. The reaction mixture was stirred at rt for 1 h, the reaction mixture was 10% Na ₂ CO ₃ solution was treated and the product extracted with EtOAc. The organic phase was dried (MgSO _4), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: DCM / MeOH 100/0 to 95/5). Yield: 0.29 g of intermediate 15 (39%).

Example A9 Preparation of intermediates 16

3-OH-bromo-2-pyridinamine (50 g, 289 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (75.3 g, 346.8 mmol) of EtOH (300 mL) The mixture was heated at 75 ° C for 17 hours. The reaction mixture was cooled to rt. EtOAc (EtOAc) The corresponding filtrate was concentrated to a volume of 100 ml. EtOH (20 mL) and DIPE (100 mL) were added to the concentrate, which caused the product to precipitate. The solid was filtered, washed with a mixture of EtOAc EtOAc (EtOAc) The combined filtrate parts 1 and 2, and stirred with saturated aqueous NaHCO ₃ (500 mL) for 30 minutes, the mixture was extracted with DCM (500 mL), the organic layer was separated dried (Na ₂ SO _4), filtered and the solvent Evaporation in vacuo, EtOAcqqqqqqq Yield: 46.5 g of intermediate 16 (55%).

Example A10 a) Preparation of intermediate products 17

A solution of 8 M methylamine in ethanol (100 mL, 0.8 mol) was added to 1-bromo-3-fluoro-2-nitro-benzene (19.8 g, 90 mmol). The mixture was cooled in water and stirred at room temperature overnight. The solvent was then evaporated and the residue was partitioned between water and DCM. Combined organic layers were dried (MgSO _4), filtered and concentrated in vacuo. Yield: 20 g of intermediate 17 (96%) was used in the next step.

b) preparation of intermediate products 18

Intermediate 17 (20 g, 86.6 mmol) and iron powder (15 g, 269 mmol) were added to acetic acid (150 mL), and the resulting suspension was stirred and heated at 60 ° C for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was distributed between DCM and saturated aqueous NaHCO _3. The organic layer was dried (MgSO _4), filtered and concentrated in vacuo. Yield: 14 g of intermediate 18 (80%) for use in the next step.

c) preparation of intermediate products 19

Et ₃ N (8.1 g, 80 mmol) was added to a solution of intermediate 18 (10 g, 39.8 mmol) in DCM (250 mL). Subsequently, at room temperature was added dropwise 4-fluoro - benzoyl chloride (5.5 g, 34.7 mmol mole) the organic layer, and the reaction mixture was stirred overnight at room temperature, the reaction mixture was washed with water, and dried (MgSO ₄₎ Filtered and concentrated in vacuo. The residue was dissolved in EtOAc (EtOAc)EtOAc The reaction mixture was stirred for 2 hours at 100 deg.] C, the reaction mixture was concentrated in vacuo, and the residue was dissolved in DCM, and washed with saturated aqueous NaHCO ₃ and water. The organic layer was dried (MgSO _4), filtered and concentrated in vacuo. Yield: 12 g of intermediate 19 for use in the next step.

Example A11 Preparation of intermediate product 20

4,4,4-Trifluorobutyraldehyde (1.891 g, 15 mmol) was added dropwise at room temperature to intermediate containing 18 (3.015 g, 15 mmol) and sodium metabisulfite (3.707 g, 19.5 mmol) The DMA (80 ml) solution of the ear was reacted in a microwave at 220 ° C for 45 minutes. The reaction mixture was diluted in EtOAc, and the organic layer was washed with H ₂ O, dried (MgSO _4), filtered and the solvent was evaporated. The residue was purified by RP preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ HCO ₃ aq) / MeOH gradient of]. The product filtrate was collected and collected for inspection. Yield: 0.670 g of intermediate 20 (14.5%).

Example A12 Preparation of intermediates 21

A mixture of 3-bromo-2-pyridinamine (1 g, 5.78 mmol) and 2-bromo-1-phenyl-1-propanone (1.48 g, 6.94 mmol) in EtOH (20 mL) was stirred. was heated at 100 ℃ 2 days, the solvent was evaporated in vacuo, and the residue was purified by chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 98/2). The product fractions were collected and the solvent was evaporated, and the residue was purified by RP preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ HCO ₃ aq) / MeOH gradient of]. The product fractions were collected and tested, yield: 0.850 g of intermediate product 21 (51%).

Example A13 a) Preparation of intermediates 22

The MeOH (100 mL) was added under N ₂ pressure to Pt / C 5% (1 g), followed by the addition containing DIPE 0.4% of thiophene (2 ml) and 4-amino-2-bromo-3- nitro Base-pyridine (3.5 g, 16 mmol) was stirred at 25 ° C under H ₂ pressure until 3 equivalents of H _{2 were taken} . The catalyst was filtered off on celite and the filtrate was concentrated in vacuo. Yield: 1.8 g of intermediate 22 (63%) for use in the next step.

b) Preparation of intermediates 23

A mixture of intermediate product 22 (1.8 g, 9.57 mmol) and 4-fluoro-benzoic acid (1.34 g, 9.57 mmol) of polyphosphoric acid (25 g) was stirred and heated at 180 ° C for 1 hour. The reaction mixture was cooled to room temperature and water was added. The resulting solution was neutralized with K ₂ CO ₃ and the resulting precipitate was filtered off and washed with water. Yield: 1 g of crude intermediate 23 was used in the next step.

c) preparation of intermediate products 24

Intermediate 23 (825 mg, 2.8 mmol), CH ₃ I (400 mg, 2.8 mmol), and K ₂ CO ₃ (830 mg, 6 mmol) was added to DMF (25 ml). The resulting mixture was stirred at 50 ° C for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was distributed between DCM and water, the organic layer was dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by RP preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ HCO ₃ aq) / MeOH gradient of]. The product filtrate was collected and tested. Yield: 180 mg of intermediate 24 (21%).

Example A14 a) preparation of intermediate products 25

1-Methyl-4-pyrazolylboronic acid (0.63 g, 4.99 mmol) and Cs ₂ CO ₃ (3.257 g, 9.99 mmol) were added to 2-bromo-5-nitromethoxybenzene ( 1.16 g, 4.99 mmol, palladium acetate (II) (0.112 g, 0.5 mmol) and triphenylphosphine (0.262 g, 1 mmol) in THF (20 mL). After stirring for 10 minutes, a 3 N NaOH solution (1.6 mL) was added and the mixture was rinsed with N _{2 for} 2 min. The reaction mixture was stirred at room temperature overnight, and the product was extracted with EtOAc, the organic layer was washed with H ₂ O, dried (MgSO _4), filtered and evaporated. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc:EtOAc: Yield: 0.630 g of intermediate 25 (54%).

b) preparation of intermediate products 26

Under N ₂ gas pressure MeOH (100 mL) was added to Pd / C 10% (0.2 g), followed by addition of 0.4% thiophene of DIPE solution (0.5 ml) and intermediate 25 (0.926 g, 3.97 mmol) . The reaction mixture was stirred at 50 ° C under H ₂ pressure until 3 equivalents of H _{2 were taken} . The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. The residue was diluted in DCM and the organic layer was washed with H ₂ O, dried (MgSO _4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on hydrazine gel (eluent: DCM / MeOH 100/0 to 90/10). The product fractions were collected and the solvent was evaporated, yield: <RTIgt;

Example A15 a) Preparation of intermediates 27

First add K ₂ CO ₃ (36 g, 262 mmol), then add 1-methyl-1-p-toluenesulfonylmethylisocyanide (35 g, 167 mmol) to 5-nitro A solution of pyridine-2-carbaldehyde (131 mmol) in MeOH (500 mL). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM, and the organic phase was washed with H ₂ O, dried (Na ₂ SO _4), filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAcEtOAcEtOAc Yield: 15 g of intermediate product 27 (56%).

b) Preparation of intermediate product 28

Containing Intermediate 27 (10 g, 48.7 mmol) of THF (300 ml) was added to a solution of ammonium chloride (2.6 g, 48.7 mmol) of H ₂ O (100 ml). Iron (16.3 g, 292 mmol) was then added and the reaction mixture was refluxed for 4 h. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in EtOAc and the organic layer was washed with H ₂ O, dried (Na ₂ SO _4), filtered, and the solvent was evaporated in vacuo. The residue was dissolved in 2N HCl solution, and the aqueous phase washed with DCM, basified by the addition of 2N NaOH solution, and the product was extracted with EtOAc, the organic layer was washed, dried (Na ₂ SO _4), filtered and the solvent in vacuo Evaporation to give 6 grams of intermediate product 28 (71%).

Example A16 a) Preparation of intermediates 29

Will contain 5-bromo-2-nitropyridine (5 g, 24.63 mmol), tributyl (1-ethoxyvinyl) tin (9.785 g, 27.1 mmol) and Ph(PPh ₃ ) ₄ (0.284 g, 0.246 mmol) of DMF (100 mL) mixture was stirred at 120 ° C for 3 hr. After cooling, 1N HCl solution was added and the mixture was stirred at room temperature for 18 hr. The reaction mixture was neutralized with saturated aqueous NaHCO _3, and the product was extracted with DCM, dried (Na ₂ SO ₄₎ organic phase was filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc:EtOAc Yield: 3.44 g of intermediate 29 (83%).

b) preparation of intermediate product 30

At room temperature, iodobenzene diacetate (2.327 g, 7.2 mmol) and trifluoromethanesulfonic acid (2.397 ml, 27.1 mmol) under N ₂ was stirred in CH ₃ CN (50 mL) for 20 minutes at at room temperature was added immediately containing intermediate 29 (1 g, 6.0 mmol) of CH ₃ CN (10 ml) was added and the reaction mixture was refluxed for 2 hours. After cooling, excess CH ₃ CN was removed under reduced pressure and the crude product was extracted with DCM. The organic layer was washed with Na ₂ CO ₃ saturated solution, dried (MgSO _4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc:EtOAc The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 0.73 g of Intermediate 30 (47%).

c) preparation of intermediates 31

Under N ₂ pressure, the MeOH (150 mL) was added to Pd / C 10% (0.5 g), followed by the addition containing DIPE was 0.4% thiophene of (2 mL) and Intermediate 30 (2.2 g, 10.7 mmol ). The reaction mixture was stirred at 50 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were} absorbed. The catalyst was filtered off on celite, and the filtrate was evaporated, yield: 1.6 g of Intermediate 31 (68%).

Example A17 a) Preparation of intermediates 32

Add isopropylamine (12.9 g, 218 mmol) to a solution containing 1-bromo-3-fluoro-2-nitro-benzene (8.0 g, 36 mmol) in EtOH (40 mL). Stir overnight at room temperature. The solvent was then evaporated and the residue was partitioned between water and DCM. Combined organic layers were dried (MgSO _4), filtered and concentrated in vacuo. Yield: 8.3 g of intermediate 32 (88%) used in the next step.

b) Preparation of intermediates 33

Intermediate 32 (8.3 g, 32 mmol) and iron powder (8.95 g, 160 mmol) were added to acetic acid (50 mL), and the resulting suspension was stirred and heated at 60 ° C for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was distributed between DCM and saturated aqueous NaHCO _3, the organic layer was dried (MgSO _4), filtered and concentrated in vacuo. Yield: 7.5 g of intermediate 33 (100%), This is used in the next step.

c) preparation of intermediates 34

4-Fluoro-benzaldehyde (2.28 g, 18.3 mmol) and Na ₂ S ₂ O ₅ (3.73 g, 19.6 mmol) were added to DMA containing intermediate 33 (3 g, 13.1 mmol). 50 ml) solution. The reaction mixture was stirred at room temperature overnight, then the reaction mixture was poured into water to give a solid precipitate, which was filtered, washed with water and suspended in DIPE. The resulting solid was filtered off, washed with DIPE and dried. Yield: 2.3 g of intermediate 34 (53%).

Example A18 a) Preparation of intermediates 35

2-iodo-5-nitromethoxybenzene (0.675 g, 2.42 mmol), Ag ₂ CO ₃ (1.11 g, 4.0 mmol), [1,1'-bis(diphenylphosphine) Ferrocene]dichloropalladium(II) (0.073 g, 0.101 mmol) and PPh ₃ (0.053 g, 0.20 mmol) were thoroughly mixed. 2-methylthiazole (0.2 g, 2.02 mmol), after addition of CH ₃ CN (10 ml), and the mixture was flushed with N _{2 2} min. The reaction mixture was stirred at 60 ° C overnight. EtOAc (EtOAc) The filtrate was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjjjjjj (51%).

b) preparation of intermediates 36

Intermediate 35 (0.25 g, 1 mmol) and iron (0.278 g, 5 mmol) were shaken in AcOH (6 mL) for 1.5 h. The solvent was evaporated, the residue was charged in DCM, and the organic layer was washed with 1N NaOH solution, dried (MgSO _4), filtered, and concentrated under reduced pressure. Yield: 0.220 g of intermediate 36 (100%).

Example A19 a) Preparation of intermediate product 37

A suspension containing 2-methoxy-4-nitro-benzoic acid (4.0 g, 20.3 mmol), SOCl ₂ (4.72 mL, 64.9 mmol), CHCl ₃ (20 mL) and one drop of DMF was refluxed 6 hours. After cooling, the solvent was removed under reduced pressure and crude crude oil was used in the next step without further purification. Yield: 4.4 g of intermediate 37 (100%).

b) Preparation of intermediates 38

A solution of intermediate product 37 (4.374 g, 20.3 mmol) and acetoguanidine (1.653 g, 22.32 mmol) in pyridine (50 ml) was refluxed overnight. After cooling, solvent was evaporated and residue was dissolved. DCM. The organic layer was washed with H ₂ O, dried (MgSO _4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc).

c) Preparation of intermediates 39

Intermediate 38 (0.2 g, 0.85 mmol) and tin (II) chloride dihydrate (0.959 g, 4.25 mmol) were stirred in EtOH (5 mL) After cooling, the reaction mixture was poured into saturated Na ₂ CO ₃ solution (15 ml) and DCM (8 ml) in. The two phases were separated and the aqueous phase was extracted with DCM. Combined organic layers were dried (MgSO _4), filtered, and concentrated under reduced pressure. Yield: 0.153 g of intermediate 39 (87%).

Example A20 a) Preparation of intermediate product 40

2M solution of methylamine in THF (0.80 g, 25.9 mmol) was added at 0 °C to 2,4-dichloro-3-nitropyridine (5.0 g, 25.9 mmol) and Et ₃ N ( 4 ml, 28.9 mmoles of a mixture of DMF (15 ml). The reaction mixture was stirred at room temperature for 1 hour, then poured into ice water, and the obtained solid was filtered, washed with H ₂ O and dried under vacuum. Yield: 3.0 g of intermediate 40 (62%).

b) Preparation of intermediate product 41

4-Fluorobenzaldehyde (1.74 g, 14.08 mmol) and Na ₂ S ₂ O ₄ (8.3 g, 47.7 mmol) were added to the intermediate product 40 (2.5 g, 13.32 mmol) of EtOH (60) ML) solution. The reaction mixture was heated at 150 ° C for 45 minutes under microwave conditions. The reaction mixture was cooled to room temperature and filtered over EtOAc. The filtrate was evaporated and the residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 99/1). The product fractions were collected and the solvent was evaporated, yield: 0.44 g, Intermediate 41 (13%).

Example A21 a) Preparation of intermediates 42

Trifluoromethanesulfonate (2.39 mL, 27.0 mmol) was added to a solution of iodobenzene diacetate (2.32 g, 7.21 mmol) of CH ₃ CN (60 ml), and the reaction mixture under a N ₂ stirred for 20 minutes at room temperature, at room temperature was added immediately containing 2'-fluoro-4'-nitro - acetophenone (1.1 g, 6.0 mmol) of CH ₃ CN (10 ml) to the solution, and then the reaction mixture was refluxed for 2 hours, then cooled to room temperature and evaporated CH ₃ CN, and the residue was extracted with DCM, washed organic phase with saturated aqueous NaHCO _3, dried (MgSO _4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent: DCM). Yield: 0.75 g of intermediate 42 (53%). b) Preparation of intermediates 43

The MeOH (50 mL) was added under N ₂ pressure to Pd / C 10% (0.2 g), followed by the addition containing DIPE was 0.4% thiophene of (1 mL) and Intermediate 42 (0.7 g, 3.15 mmol) . The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were taken} . The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. Yield: 0.6 g of intermediate 43 (77%).

Example A22 a) Preparation of intermediates 44

Will contain 2-iodo-5-bromopyridine (13.7 g, 48.2 mmol), 2-methyl-4- Methyl azole carboxylate (3.4 g, 24.1 mmol), palladium (II) acetate (0.54 g, 2.41 mmol) tri-o-tolylmethylphosphonium phosphide (1.47 g, 4.81 mmol) and Cs ₂ CO ₃ (15.7 g, 48.2 mmol) of toluene (75 mL) was treated with N ₂ flushed, sealed and stirred overnight at 110 ℃. The catalyst was filtered on diatomaceous earth and the filtrate was evaporated. The crude product was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 98/2), parts of the product was collected by filtration and the solvent was evaporated Yield: 5.64 g of intermediate Product 44 (13%).

b) Preparation of intermediate product 45

Intermediate product 44 (5.64 g, 15.4 mmol) and LiOH (0.91 g, 38 mmol) were dissolved in two Dioxane (40 ml) with ₂ O (10 ml) in a mixture of H. The reaction mixture was stirred at room temperature for 5 hours and then treated with 1 M HCl solution until pH = 2. The precipitate obtained was filtered and dried under vacuum. The filtrate was extracted with CHCl _3, and the organic layer was dried (MgSO _4), filtered and the solvent removed under reduced pressure to give a solid, two solids were combined and filtered. Yield: 4.75 g of intermediate 45 (97%).

c) preparation of intermediates 46

Copper (II) oxide (1.33 g, 16.8 mmol) was added to a solution of intermediate 45 (4.75 g, 16.8 mmol) in DMF (75 mL). After cooling, the catalyst was filtered on diatomaceous earth and the filtrate was evaporated. The residue was developed in ₃ CN DIPE / CH, and the resulting solid was filtered off. The filtrate was evaporated and the residue was used in the next step. Yield: 1 g of intermediate 46 (14.5%).

d) preparation of intermediate products 47

Intermediate 46 (0.53 g, 2.23 mmol), Pd ₂ (dba) ₃ (0.204 g, 0.223 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.212 g, 0.446 mmol) and Cs ₂ CO ₃ (2.18 g, 6.69 mmol) were added to the N -benzylamine containing A solution of (0.239 g, 2.23 mmol) in 2-methyl-2-propanol (20 mL). After cooling, H ₂ O was added and the product was extracted with DCM. Dried (MgSO ₄₎ organic phase was filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography to step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 98/2), and the product was filtered off were collected and the solvent was evaporated. Yield: 0.15 g of intermediate product 47 (21%).

e) Preparation of intermediates 48

The MeOH (50 mL) was added under N ₂ pressure to Pd / C10% (0.05 g), followed by addition of Intermediate 47 (0.15 g, 0.565 mmol). The reaction mixture was stirred at 50 ° C under a pressure of H ₂ until 1 equivalent of H _{2 was} absorbed. The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. Yield: 0.105 g of intermediate product 48 (95%).

Example A23 a) Preparation of intermediates 49

1M solution of LiHMDS in THF (47 ml, 47 mmol) was added dropwise at 0 ° C under N ₂ pressure to 5-(4-nitrophenyl)- A solution of azole (6.0 g, 31.6 mmol) in THF (100 mL). The reaction mixture was stirred at 0&lt;0&gt;C for 30 min then EtOAc (EtOAc &lt The reaction mixture was stirred at room temperature for 1 hour and then added MeOH (100 mL) and NaBH ₄ (1.55 g, 41 mmol). The reaction mixture was stirred at room temperature for 16 hours and then the solvent was removed in vacuo part, adding H ₂ O, was added and the mixture was neutralized with AcOH, the mixture was extracted with DCM, the organic phase separated, dried (MgSO _4), filtered, and The solvent was evaporated in vacuo and the residue was crystallised from DIPE. Yield: 4.6 g of intermediate 49 (61%).

b) preparation of intermediates 50

The containing of 60% NaH in mineral oil (600 mg, 15 mmol) was added to a solution of intermediate 49 N ₂ at atmospheric pressure (1.79 g, 7.5 mmol) of THF (61 mL). The reaction mixture was stirred at room temperature for 30 minutes then add CH ₃ I (1.87 mL, 30 mmol). The reaction mixture was stirred at 60 ° C for 4 hours and then brine was added. The organic phase was separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. Yield: 790 mg of intermediate 50 (41%).

c) Preparation of intermediate product 51

MeOH (100 mL) was added to Pd/C 10% (0.2 g) under N ₂ atmosphere, then DIPE solution (0.5 mL) containing 0.4% thiophene and intermediate product 50 (0.79 g, 3.1 mmol). . The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were taken} . The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. Yield: 0.65 g of intermediate 51 (quantitative).

Example A24 a) Preparation of intermediate product 52

Will contain N- (5-bromo-1,6-dihydro-6-keto-2-pyridyl)-acetamide (8.6 g, 37.2 mmol), CH ₃ I (13.2 g, 93 mmol) The mixture of toluene (275 ml) of Ag ₂ CO ₃ (10.2 g, 3.2 mmol) was stirred at 60 ° C for 48 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between DCM and H ₂ O, the organic phase separated, dried (MgSO _4), filtered, and the solvent was evaporated in vacuo. The residue was triturated with DIPE. Yield: 5.7 g of intermediate 52 (62%).

b) Preparation of intermediates 53

1-methyl-4-pyridyl Bora boronic acid pinacol ester (1.96 g, 9.4 mmol) and Pd(PPh ₃ ) ₄ (0.835 g, 0.72 mmol) were added to DMF containing intermediate product 52 (1.77 g, 7.2 mmol). ML), H ₂ O (5 mL) and K ₂ CO ₃ (2.0 g, 14.4 mmol) solution. The reaction mixture was degassed, placed under N ₂ gas, stirred and heated at 140 ° C for 30 min under microwave. The reaction mixture was cooled to room temperature, distributed between DCM and H ₂ O, the organic phase separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo, the residue was triturated in CH ₃ CN. Yield: 1.35 g of intermediate 53 (76%).

c) preparation of intermediate products 54

A 10% aqueous NaOH solution (50 mL) was added to MeOH (EtOAc) (EtOAc,EtOAc. The organic solvent was removed in vacuo and DCM and H ₂ O, the organic phase separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo, the residue in DIPE developed. Yield: 0.95 g of intermediate 54 (88%).

Example A25 Preparation of intermediates 55

Add 2-methylpyridine-4-boronic acid pinacol ester (3178 mg, 14.5 mmol) and Pd(PPh ₃ ) ₄ (1.22 g, 1.06 mmol) to 2-bromo-5-nitro-methyl Oxybenzene (3.06 g, 13.2 mmol) in DME (40 mL), water (16 mL) and Cs ₂ CO ₃ (1.33 g, 40.9 mmol), the resulting mixture was stirred at reflux temperature Heat for 16 hours. The reaction mixture was cooled to room temperature and distributed between H ₂ O and DCM. The organic phase was separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was purified on a hydrazine gel by flash column chromatography (eluent: DCM / MeOH 100/0 to 98/2). The product fractions were collected and concentrated in vacuo to give &lt;RTIgt;

b) Preparation of intermediates 56

Intermediate 55 (2.04 g, 9.50 mmol) was added to 10% Pd / C (500 mg) was stirring mixture of containing and containing MeOH 4% thiophene of (1 mL), the reaction mixture under H ₂ pressure After heating at 50 ° C, 3 equivalents of H ₂ were absorbed, the catalyst was filtered off on diatomaceous earth, the filtrate was evaporated under reduced pressure, and the crude product was purified by column chromatography on hydrazine gel (eluent: MeOH /DCM 10/90). The product fractions were combined and evaporated to give a brown solid. Yield: 1700 mg of intermediate 56 (95%).

Example A26 Preparation of intermediates 57

Trifluoromethanesulfonate (7.63 ml, 86 mmol) was added to CH containing iodobenzene diacetate (7.41 g, 23 mmol) of ₃ CN (50 ml) was added and the reaction mixture under a N ₂ Stir at room temperature for 20 minutes. A solution of 1- (2-chloro-5-pyrimidinyl) - ethanone (3 g, 19.2 mmol) of CH ₃ CN (10 ml) was added immediately to the solution at room temperature, then the reaction mixture was refluxed for 2 h, then cooled to room temperature and evaporated CH ₃ CN, and the residue was extracted with DCM, washed organic phase with saturated aqueous NaHCO _3, dried (MgSO _4), filtered and the solvent evaporated under reduced pressure. The residue was purified on a hydrazine gel by flash column chromatography (eluent: DCM), product fractions were collected, and the solvent was evaporated under reduced pressure. Yield: 1.6 g of intermediate 57 (43%).

Example A27 a) Preparation of intermediates 58

A mixture of 1-ethynyl-2-methoxy-4-nitro-benzene (785 mg, 4.43 mmol) and trimethyldecyl azide (1.75 mL, 13.3 mmol) was divided into 6 Microwave vials were heated at 150 ° C for 2 hours under microwave irradiation. The reaction mixture was cooled to room temperature and filtered over using DCM diatomaceous earth, filtrate was washed with H ₂ O. The organic phase was separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was purified on a hydrazine gel by flash column chromatography (eluent: DCM / MeOH 100/0 to 96/4). The product fractions were collected and concentrated in vacuo to yield 344 <RTIgt;

b) preparation of intermediate product 59 and intermediate product 60

K ₂ CO ₃ (580 mg, 4.2 mmol) was added to a THF (10 mL) EtOAc. The mixture was cooled to 0-5 ° C and CH ₃ I (0.131 mL, 2.1 mmol). The reaction mixture was stirred at room temperature for 3 hr. The organic phase was separated, dried (MgSO _4), filtered, and the solvent was evaporated in vacuo. The residue was purified in a preparative SFC (AD chiral pak Diacel 20 x 250 mm; mobile phase CO _2, MeOH containing 0.2% iPrNH _2). The product fractions were collected and concentrated in vacuo to yield: </ RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt;

c) preparation of intermediate products 61

Was added MeOH (40 mL) under N ₂ pressure to Pd / C 10% (0.05 g), followed by the addition containing DIPE was 0.4% thiophene of (0.1 ml) and intermediate 59 (0.214 g, 0.91 mmol). The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were taken} . The catalyst was filtered off over diatomaceous earth, and the filtrate was evaporated, the residue was distributed between DCM and H ₂ O, the organic phase separated, dried (MgSO _4), filtered and the solvent evaporated in vacuo. Yield: 0.198 g of intermediate product 61 (98%).

d) preparation of intermediate product 62

MeOH (40 ml) was added to Pd/C 10% (0.05 g) under N ₂ atmosphere, and then DIPE solution (0.1 ml) and intermediate product 60 (0.070 g, 0.3 mmol) containing 0.4% thiophene were added. The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were taken} . Filtered off the catalyst on diatomaceous earth, and the filtrate was evaporated, the residue was distributed between DCM and water, the organic phase separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. Yield: 0.073 g of intermediate 62 (quantitative).

Example A28 Preparation of intermediates 63

The stainless steel pressure cooker was filled with intermediate product 19 (370 mg, 1.21 mmol), cuprous oxide (I) (10 mg), and containing 0.5 M NH ₃ A solution of alkane (30 ml, 15 mmol). The autoclave was closed and the reaction mixture was heated at 150 °C for 18 hours. Then, the reaction mixture was cooled, a saturated aqueous solution of NH ₄ OH (5 ml) was added, and the reaction mixture was heated at 150 ° C for another 18 hours. The reaction mixture was cooled and the reaction mixture was concentrated in vacuo. The residue was partitioned between DCM and saturated aqueous NH ₄ Cl. The organic layer was dried (MgSO _4), filtered and concentrated in vacuo. Yield: 240 mg of intermediate 63 (82%) for use in the next reaction.

Example A29 a) Preparation of intermediates 64

Add Na ₂ S ₂ O ₅ (1.64 g, 8.62 mmol) and 4-fluoro-benzaldehyde (891 mg, 7.18 mmol) to 3-bromo-5-trifluoromethyl-1,2- Diaminobenzene (1.65 g, 6.47 mmol) in DMA (40 mL). The reaction mixture was stirred at 70 ° C overnight, then the reaction mixture was cooled to room temperature and poured into water. The solid was filtered off, washed with water and suspended in DIPE and a few drops of 2-propanol. The resulting solid was filtered off, washed with DIPE and dried. Yield: 1.95 g of intermediate 64 (84%).

b) Preparation of intermediate product 65

The sum of THF containing 1M LiHMDS (9.2 mL, 9.2 mmol) was added at room temperature under N ₂ pressure, added dropwise to a mixture of intermediate product 64 (1.65 g, 4.6 mmol) of THF (50 ml). The reaction mixture was stirred at room temperature for 30 minutes, then add CH ₃ I (3.26 g, 23 mmol), the reaction mixture was stirred at room temperature for 1 hour and then washed with saturated aqueous NaHCO ₃ and brine, the organic phase separated, dried (MgSO ₄ ), filter and evaporate the solvent in vacuo. The residue was purified by RP preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ HCO ₃ aq) / MeOH / CH ₃ CN gradient of]. The product filtrate was collected and tested. Yield: 720 mg of intermediate 65 (42%).

Example A30 a) Preparation of intermediates 66

Add Na ₂ S ₂ O ₅ (5.56 g, 29.2 mmol) and 4-fluoro-benzaldehyde (2.91 g, 23.4 mmol) to 3-bromo-5-fluoro-1,2-diamino group Benzene (4.0 g, 19.5 mmol) in DMA (80 mL). The reaction mixture was stirred at 70 ° C overnight. The reaction mixture was then cooled to room temperature and poured into water. The solid was filtered off, washed with water and dried. Yield: 6 grams of intermediate 66, which was used in the next reaction step.

b) Preparation of intermediates 67

THF (5 containing of 60% NaH in mineral oil (233 mg, 5.82 mmol) was N ₂ at atmospheric pressure, was added to a cold (5 ℃) containing Intermediate 66 (900 mg, 2.91 mmol) of ML) solution. The reaction mixture was stirred at 5 ° C for 30 minutes and then isopropyl iodide (1.98 g, 11.6 mmol) was added. The reaction mixture was stirred at 130 ° C for 2 hours under microwave conditions. The reaction mixture was cooled, additional THF was added and the mixture was washed with brine. The organic phase was separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was purified on a hydrazine gel by flash column chromatography (eluent: heptane / DCM 50/50 to 0/100). The product fractions were collected and the solvent was evaporated, yield: 350 mg of intermediate 67 (34%).

Example A31 a) Preparation of intermediate product 68

N -iodosuccinimide (26.7 g, 119 mmol) and TFA (2.5 mL, 32.4 mmol) were added to 2,4-dichloro-pyridin-3-ylamine (17.6 g, 108 m) mole) of CH ₃ CN (150 ml) solution, the reaction mixture was stirred for 16 hours at room temperature, then heated to 40 ℃ 6 hours. The reaction mixture was diluted with EtOAc, and washed with Na ₂ S ₂ O ₃ saturated aqueous solution. The aqueous phase was extracted with EtOAc, and the combined organic layers were dried (MgSO _4), filtered and the solvent evaporated in vacuo. The residue was purified on a hydrazine gel by flash column chromatography (eluent: DCM). Yield: 22 g of intermediate 68 (71%).

b) preparation of intermediate product 69 and intermediate product 70

A solution of methylamine in THF (2M, 25 mL, 50 mmol) was added to a solution of Intermediate 68 (4.8 g, 16.6 mmol) in EtOH (20 mL). Stir at 160 ° C for 8 hours. Then, the solvent was evaporated, and the residue was partitioned between aqueous NaHCO ₃ and DCM. Dried (Na ₂ SO ₄₎ the organic layers were combined, filtered, and concentrated in vacuo. The residue was purified on a hydrazine gel by flash column chromatography (eluent: heptane / DCM 100/0 to 0/100). The product fractions were collected and the solvent was evaporated, yield: 950 mg of intermediate product 69 (20%) and 2900 mg of intermediate product 70 (62%).

c) Preparation of intermediate product 71

Et ₃ N (3.61 mL, 26.5 mmol) and 4-fluoro-benzylguanidinium chloride (1.68 g, 10.6 mmol) were added to DCM (100 g, 2.5 g, 8.8 mmol). In ML) solution, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to yield 2.7 g of crude intermediate 71 (75%).

d) preparation of intermediates 72

Add phosphonium chloride (907 mg, 5.9 mmol) to a solution of intermediate 71 (2.0 g, 4.93 mmol) in dichloroethane (15 mL) and stir the mixture and It was heated at 150 ° C for 0.25 hours under microwave irradiation. The reaction mixture was concentrated in vacuo, and the residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 97/3). The product fractions were collected and the solvent was evaporated, yield: 1.56 g of intermediate product 72 (81%).

e) Preparation of intermediate product 73

Adding isopropenylboronic acid pinacol ester (867 mg, 5.16 mmol) and Pd(PPh ₃ ) ₄ (298 mg, 0.258 mmol) to intermediate containing 72 (2.0 g, 5.16 mmol) two Dioxane (8 ml) and aqueous NaHCO ₃ (4 ml), the resulting mixture was the stirred and heated to 160. deg.] C under microwave irradiation for 10 min. The reaction mixture was cooled to room rt and filtered over EtOAc EtOAc. The residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 97/3), parts of the product was collected by filtration and the solvent was evaporated. Yield: 1.25 g of intermediate product 73 (80%).

f) Preparation of intermediate product 74

The MeOH (40 mL) was added under N ₂ pressure to Pt / C5% (100 mg), followed by addition of Intermediate 73 (1.25 g, 4.14 mmol). The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 1 equivalent of H _{2 was taken} . The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. Yield: 0.9 g of crude intermediate 74 (71%) used in the next reaction.

g) Preparation of intermediate product 75

Methylboronic acid (93 mg, 1.55 mmol) and Pd(PPh ₃ ) ₄ (71 mg, 0.062 mmol) were added to intermediate product 72 (600 mg, 0.31 mmol). Dioxane (10 mL) and aqueous NaHCO ₃ (5 ml) solution. The resulting mixture was stirred and heated at 150 ° C for 20 minutes under microwave irradiation. The reaction mixture was cooled to room temperature and distributed between water and DCM. The organic phase was separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. Yield: 180 mg of crude intermediate 75 used in the next reaction step.

h) Preparation of intermediate product 76

Zn(CN) ₂ (36 mg, 0.31 mmol) and Pd(PPh ₃ ) ₄ (30 mg, 0.026 mmol) were added to DMF containing intermediate 72 (200 mg, 0.52 mmol). lL) solution. The resulting mixture was stirred and heated at 160 ° C for 10 minutes under microwave irradiation. The reaction mixture was cooled to room temperature and filtered over EtOAc. The filtrate was concentrated in vacuo, and the residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 97/3). The product fractions were collected and the solvent was evaporated, yield: <RTI ID=0.0># </RTI>

Example A32 a) Preparation of intermediates 77

4-Fluorobenzaldehyde (1.11 g, 8.93 mmol) and Na ₂ S ₂ O ₄ (3.89 g, 22.3 mmol) were added to the 2-chloro- N -6-dimethyl-3-nitro group. A solution of pyridin-4-amine (1.5 g, 7.44 mmol) in EtOH (15 mL). The reaction mixture was heated at 160 ° C for 1 hour under microwave conditions. The reaction mixture was cooled to rt and filtered over EtOAc EtOAc EtOAc. The combined filtrates were evaporated, and the residue was purified by RP preparative HPLC [RP Vydec Denali C18 (10 μm, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ HCO ₃ aqueous solution) / CH ₃ CN gradient ], collect the product filtrate and test. Yield: 1.95 g of intermediate 77 (32%).

Example A33 a) Preparation of intermediate products 78

Et ₃ N (1.87 ml, 13.8 mmol) and 4-fluoro-benzimid chloride (873 mg, 5.5 mmol) were added to DCM (80 g, 4.6 m. (ml) solution and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to yield 1.5 g of crude intermediate 78 (81%).

b) Preparation of intermediate product 79

Phosphorus chloride (121 mg, 0.79 mmol) was added to a solution of intermediate 78 (267 mg, 0.66 mmol) in dichloroethane (2 mL), and the mixture was stirred under microwave. Heat at °C for 0.25 hours. The reaction mixture was concentrated in vacuo, and the residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 97/3). The product fractions were collected and the solvent was evaporated <RTI ID=0.0>

c) Preparation of intermediate product 80

Adding isopropenylboronic acid pinacol ester (434 mg, 2.58 mmol) and Pd(PPh ₃ ) ₄ (149 mg, 0.129 mmol) to intermediate product 79 (1.0 g, 2.58 mmol) two Dioxane (8 ml) and aqueous NaHCO ₃ (4 ml), and the mixture arising stirred and heated under microwave irradiation at 160 ℃ 10 minutes. The reaction mixture was cooled to room rt and filtered over EtOAc EtOAc. The residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 97/3). The product fractions were collected and the solvent was evaporated, yield: <RTIgt;

d) Preparation of intermediate product 81

N ₂ gas pressure in MeOH (40 mL) was added to Pt / C 5% (100 mg), followed by addition of Intermediate 80 (0.75 g, 2.49 mmol). The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 1 equivalent of H _{2 was taken} . The catalyst was filtered off on diatomaceous earth and the filtrate was evaporated. Yield: 0.55 g of crude intermediate 81 (73%) used in the next reaction.

e) Preparation of intermediate product 82

Cyclopropylboronic acid (86 mg, 1.0 mmol) and Pd(PPh ₃ ) ₄ (78 mg, 0.067 mmol) were added to intermediate product 79 (260 mg, 0.67 mmol). Dioxane (6 ml) and _aqueous solution (3 ml) NaHCO mixture was stirred and heated under microwave irradiation at 160 ℃ 10 minutes. The reaction mixture was cooled to room temperature and filtered over EtOAc EtOAc EtOAc. The residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 97/3). The product fractions were collected and the solvent was evaporated, yield: &lt;RTI ID=0.0&gt;

Example A34 a) Preparation of intermediates 83

Phosphorium chloride (1.25 ml, 13.7 mmol) was added to DMF (3.5 mL) at 0 ° C, and the mixture was stirred at this temperature for 0.5 hr. Intermediate 16 (1 g, 3.44 mmol) was added <RTI ID=0.0></RTI> to EtOAc. The reaction mixture was stirred at room temperature overnight, the reaction mixture was poured on ice, and NaHCO ₃ was added to neutralize mixture. The mixture was extracted with DCM, dried (MgSO ₄₎ organic layer was filtered and the solvent was evaporated in vacuo. The residue was triturated with DIPE and the solid was collected and dried. Yield: 0.625 g of intermediate product 83 (57%).

b) Preparation of intermediate product 84

The NaBH ₄ (28 mg, 0.75 mmol) was added to a solution of Intermediate 83 (200 mg, 0.63 mmol) of MeOH (5 mL) and THF (2 mL) was added. The reaction mixture was stirred at room temperature for 15 minutes and then the solvent was removed in vacuo. The residue was distributed between DCM and water, dried (MgSO ₄₎ organic layer was filtered and the solvent was evaporated in vacuo. Yield: 90 mg of intermediate 84 (45%).

c) Preparation of intermediate products 85

Thionine chloride (33 mg, 0.28 mmol) was added to DCM (2 mL) EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 30 minutes and add saturated aqueous NaHCO _3. The organic layer was separated, filtered over celite, and filtrate was concentrated. Yield: 90 mg of intermediate 85 (95%).

d) Preparation of intermediate product 86

A solution of 0.5 M NaOMe in MeOH (0.64 mL, 0.32 mmol) was taken to EtOAc (2 <RTIgt; The reaction mixture was stirred at room temperature for 30 minutes at room temperature then the solvent was removed in vacuo. The residue was partitioned between DCM and H ₂ O. The organic layer was filtered over celite and the filtrate was concentrated. The residue was triturated with DIPE and dried in vacuo. Yield: 60 mg of intermediate 86 (67%).

e) Preparation of intermediates 87

A solution of KO t Bu (0.87 g, 7.74 mmol) in THF (7 mL) was added at -15 ° C to &lt;RTI ID=0.0&gt; In a suspension of THF (3 ml). The reaction mixture was stirred for 30 minutes. Subsequently, a solution of intermediate product 83 (0.95 g, 3 mmol) in THF (3 mL). The reaction mixture was partitioned between DCM and H ₂ O. The organic layer was dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH 99/1). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 700 mg of the intermediate product 87 of E/Z mixture (68%).

Example A35 a) Preparation of intermediate product 88

1-Iodo-2,5-pyrrolidinedione (5.54 g, 24.6 mmol) was added to 8-bromo-2-(2-trifluoromethyl-phenyl)-imidazo[1,2 -a]pyridine (prepared from 3-bromo-2-pyridinamine and 2-bromo-1-(2-trifluoromethyl-phenyl)ethanone according to Example A9; 5.6 g, 16.4 mmol) DCM (50 ml). The reaction mixture was stirred at room temperature for 24 hours, diluted with additional DCM, and then washed with aqueous 15% NaOH, then washed with saturated aqueous NaHSO _3. The organic layer was dried (MgSO _4), filtered, and concentrated in vacuo. Yield: 7.2 g of intermediate 88 (94%).

b) Preparation of intermediate product 89

Will contain intermediate 88 (350 mg, 0.75 mmol), 3-methoxy-propyne (58 mg, 0.82 mmol), PdCl ₂ (PPh ₃ ) ₂ (20 mg, 0.028 mmol), CuI (5 mg, 0.027 mmol) of Et ₃ N ₍₃ ml) was stirred under N ₂ at atmospheric pressure at 50 ℃ 20 hours. The mixture was partitioned between DCM and H ₂ O, dried (MgSO ₄₎ organic layer was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH 99/1). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 100 mg of intermediate 89 (33%).

c) Preparation of intermediate product 90

Intermediate 4 (50 mg, 0.24 mmol), Pd ₂ (dba) ₃ (22 mg, 0.024 mmol), X-phos (23 mg, 0.049 mmol) and Cs ₂ CO ₃ (240 mg) , 0.73 mmol) was added under N ₂ pressure to an intermediate product containing 89 (100 mg, 0.24 mmol) of 2-methyl-2-propanol (10 ml), the reaction mixture was heated at 100 deg.] C 20 hours. Then, water was added and the mixture was extracted with DCM, dried (MgSO ₄₎ the organic layers were combined, filtered and the solvent was evaporated. The residue was purified on a silicon dioxide gel chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 99/1). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 30 mg of intermediate 90 (23%).

Example A36 a) Preparation of intermediate product 91

A mixture of 3-bromo-5-fluoro-1,2-diaminobenzene (10.5 g, 51 mmol) and urea (3.84 g, 64 mmol) in xylene (100 mL) was stirred at reflux overnight. . Subsequently, the reaction mixture was cooled to room temperature, and the resulting precipitate was filtered off. The solid was suspended in 1N aqueous HCl and filtered again and dried. The solid produced was developed in DIPE. Yield: 9.5 g of intermediate 91 (80%).

b) Preparation of intermediate product 92

Phosphorus chloride (30 ml) was slowly added to intermediate product 91 (3.0 g, 13 mmol), then concentrated aqueous HCI (1 mL). The reaction mixture was heated under reflux for 2 days, the reaction mixture was concentrated in vacuo, the residue was distributed between DCM and _aqueous NaHC03, the organic layer was dried (MgSO _4), filtered and evaporated. Yield: 3.0 g (93%) of crude intermediate 92.

c) Preparation of intermediates 93

A 60% NaH-containing mineral oil (721 mg, 18 mmol) suspension was added to a cold (5 ° C) intermediate product 92 (3.0 g, 12 mmol) DMF (40 ° C) under N ₂ pressure. ML) solution. The reaction mixture was stirred at 5 ° C for 30 minutes then CH ₃ I (8.53 g, 60 mmol). The reaction mixture was stirred at room temperature for 3 hr then partitioned between water and EtOAc. The organic phase was separated, dried (MgSO _4), filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (eluent: heptane /EtOAc /EtOAc /EtOAc /EtOAc Yield: 850 mg of intermediate 93 (27%).

d) preparation of intermediate product 94

A mixture of intermediate product 93 (760 mg, 2.88 mmol) and pyrrolidine (1.03 g, 14.4 mmol) in NMP (15 mL) was then warmed to </RTI><RTIgt; The reaction mixture was cooled to room temperature and poured into H ₂ O (100 ml), filtered off and the resulting precipitate was washed in H ₂ O. The solid was dried and DIPE was developed. Yield: 675 mg (78%) of intermediate 94.

Example A37 a) Preparation of intermediate product 95

2-Chloro-acetaldehyde (6 M, 1.0 mL, 6.0 mmol) and Na ₂ S ₂ O ₅ (1.14 g, 6.0 mmol) were added to intermediate 18 (800 mg, 3.98 mmol) A solution of DMA (10 mL) was obtained and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into H ₂ O. The solid was filtered off, washed with H ₂ O and suspended in DIPE. The solid was filtered off to wash the DIPE and dried. Yield: 0.15 g of intermediate 95 (15%).

b) Preparation of intermediate product 96

The containing of 60% NaH in mineral oil (193 mg, 4.82 mmol) was added under N ₂ to a pressure-containing 2-propanol (232 mg, 3.85 mmol) of DMF (10 mL) was added, and the reaction The mixture was stirred at room temperature for 30 minutes then the intermediate product 95 (0.5 g, 1.93 m. The reaction mixture was stirred at room temperature for 2 hours and then distributed between H ₂ O and EtOAc. The organic phase was separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 95/5), parts of the product was collected by filtration and the solvent was evaporated. Yield: 120 mg of intermediate 96 (15%).

Example A38 a) Preparation of intermediates 97

Ethyl 8-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (0.60 g 1.56 mmol) and LiOH (38 mg, 1.6 mmol) A mixture of THF/H ₂ O (10 mL / 10 mL) was then evaporated. The mixture was acidified with 1N aqueous HCl until product precipitated. The precipitate was filtered off and dried in vacuo. Yield: 0.5 g of intermediate 97 (90%).

b) Preparation of intermediates 98

A solution of 2M dimethylamine in THF (0.58 mL, 1.16 mmol) in THF (10 mL) was added to Intermediates 97 (500 mg, 1.4 mM) and HBTU (533 mg, 1.4 mM) DMF (10 ml) mixture was then added DIPEA (0.98 mL, 5.62 mmol), and the mixture was stirred at room temperature for 18 hrs, and the mixture was diluted with DCM and washed with 0.5 N aqueous NaOH and H ₂ O organic layer was dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified on a silicon dioxide gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 99/1). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 490 mg of intermediate 98 (90%).

Example A39 a) Preparation of intermediate 99

BF ₃ etherate (0.154 mL, 1.32 mmol) was added to 4-fluorophenylglyoxal hydrate (4.5 g, 26.5 mmol) and 2-amino-3-bromopyridine (4.72 g) , 26.5 mmoles in a mixture of DCM (100 mL). The reaction mixture was stirred at room temperature for 6 hours. The resulting precipitate was filtered off and dried in vacuo. Yield: 4 g of intermediate 99 (49%).

b) preparation of intermediate product 100

NaH (60% in mineral oil, 414 mg, 10.3 mmol) was added to EtOAc (EtOAc (EtOAc) The reaction mixture was stirred for 15 minutes at 0 ℃, then add CH ₃ I (0.258 mL, 4.14 mmol), and the reaction mixture was stirred overnight arising at room temperature. The reaction mixture was quenched with water and then concentrated in vacuo. The residue was partitioned between DCM and H ₂ O, the organic layer was dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: n-heptane / EtOAc 100/0 to 50/50). The product fractions were collected and the solvent was evaporated in vacuo and the residue was suspended in DIPE and dried in vacuo. Yield: 445 mg of intermediate 100 (40%).

Example A40 Preparation of intermediate product 101

3,5-dibromo-pyridyl 2-ylamine (5 g, 19.8 mmol), 2-chloro-acetone (18.3 g, 198 mmol) and two The alkane (40 mL) was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure and dichloromethane was evaporated Yield: 3.6 g of intermediate product 101 (55%).

Example A41 a) preparation of intermediate product 102

Bromine (3.15 ml, 61.3 mmol) was added dropwise at 15 ° C to a solution of 4-amino-3-nitro-benzonitrile (10 g, 61.3 mmol) in AcOH (80 mL). The reaction mixture was stirred at room temperature overnight and additional bromo (1. After another 6 hours at room temperature, additional bromine (0.79 mL, 15.3 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was evaporated The residue was purified by flash column chromatography (eluent: DCM /MeOH 98/2). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 6.24 g of intermediate product 102 (35%).

b) Preparation of intermediate product 103

4-Fluorobenzaldehyde (0.96 ml, 9.1 mmol) and Na ₂ S ₂ O ₄ (5.04 g, 28.9 mmol) were added to the intermediate product 102 (2 g, 6.86 mmol) of EtOH (10) ML) solution, the reaction mixture was heated at 150 ° C for 45 minutes under microwave conditions. The reaction mixture was cooled to room temperature and filtered over EtOAc. The filtrate was evaporated and the residue was dissolved in DMF. H ₂ O was added, and the resulting precipitate was filtered off and washed with H ₂ O. The residue was suspended in toluene and the solvent was removed under reduced pressure. Yield: 1.6 g of intermediate 103 (70%).

c) preparation of intermediates 104

The containing of 60% NaH in mineral oil (569 mg, 14.2 mmol) was added to a solution at 5 ℃ intermediate 103 (3 g, 9 mmol) of DMF (20 ml) under N ₂ gas pressure, The reaction mixture was stirred for 15 minutes at 5 ℃, then add CH ₃ I (1.48 mL, 23.7 mmol). The reaction mixture was stirred at room temperature for 30 min and distributed between EtOAc and H ₂ O, the organic phase separated, dried (MgSO _4), filtered and the solvent evaporated in vacuo. The residue was purified on a hydrazine gel by flash column chromatography (eluent: DCM / MeOH 100/0 to 99/1). The product fractions were collected and the solvent was evaporated, and the residue was purified further by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 micron, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ CO ₃ aqueous solution, CH ₃ CN /MeOH)]. The product fractions were collected and concentrated under reduced pressure. Yield: 1.1 g of intermediate product 104 (37%).

Example A42 a) Preparation of intermediate product 105

MeOH (150 ml) was added to Pt/C 5% (1 g) under N ₂ pressure, then DIPE solution (2 mL) and 2-bromo-4-methoxy-6 containing 0.4% thiophene were added. - Nitroaniline (5 g, 20.2 mmol). The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 3 equivalents of H _{2 were taken} . The catalyst was filtered off on celite and the filtrate was concentrated in vacuo. Yield: 4.33 g of the intermediate product 105 (99%) used in the next step.

b) preparation of intermediate product 106

4-Fluoro-benzaldehyde (1.17 ml, 11.1 mmol) and Na ₂ S ₂ O ₅ (2.63 g, 13.8 mmol) were added to DMA containing intermediate product 105 (2 g, 9.2 mmol). 40 ml) of the solution, the reaction mixture was stirred at 90 ° C overnight, and then the reaction mixture was poured into water to give a solid precipitate. The solid was filtered off, washed with water and suspended in DIPE. The solid that was formed was filtered, washed with DIPE and dried. Yield: 2.9 g of intermediate product 106 (98%).

c) preparation of intermediate product 107

The containing of 60% NaH in mineral oil (486 mg, 12.1 mmol) was added under N ₂ to a pressure-containing intermediate 106 (2.6 g, 8.1 mmol) of DMF (15 ml) at 5 ℃. The reaction mixture was stirred at 5 ° C for 30 minutes then methyl iodide (1.26 mL, 20.2 mmol). The reaction mixture was stirred at room temperature for 3 hours and distributed between EtOAc and water, the organic phase separated, dried (MgSO _4), filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (eluent: DCM / MeOH 100/0 to 99/1). Yield: 1.25 g of intermediate product 107 (46%).

Example A43 a) Preparation of intermediate product 108

The ₃ (12.5 mL) was added to a solution of 3,5-dibromo concentrated HNO - pyridine N- oxide (4.5 g, 17.8 mmol) of concentrated H ₂ SO ₄ (16 mL) and the reaction mixture was refluxed for 4 hours , then cool and pour on ice water. The resulting precipitate was collected by filtration and dried. Yield: 3.1 g of the intermediate product 108 (58%) was used in the next step.

b) Preparation of intermediate product 109

A solution of 2M methylamine in THF (7.15 mL, 14.3 mmol) was. The reaction mixture was stirred at 60 ° C for 2 days and then concentrated in vacuo. The residue was partitioned between DCM and _aqueous NaHC03, the organic phase separated, dried (Na ₂ SO _4), filtered and the solvent evaporated in vacuo. The residue was purified on a hydrazine gel by flash column chromatography (eluent: heptane / DCM / MeOH (NH ₃ ) 100 /0 /0 / / / / / / / / / / / The fractions were filtered and the solvent was evaporated. Yield: 1.2 g of intermediate product 109 (54%).

c) preparation of intermediate product 110

4-Fluorobenzaldehyde (252 mg, 2.0 mmol) and Na ₂ S ₂ O ₄ (1.18 g, 6.8 mmol) were added to the intermediate product 109 (420 mg, 1.7 mmol) of EtOH (6) The reaction mixture was heated at 160 ° C for 45 minutes under microwave conditions in a milliliter solution. The reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with aqueous NaHCO ₃ and brine, the organic phase separated, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 97/3). The product fractions were collected and the solvent was evaporated, yield: 0.35 g, Intermediate 110 (68%).

Example A44 Preparation of intermediate product 111

NMP containing 6-amino-5-bromo-nicotinonitrile (4 g, 20.2 mmol) and 1-bromo-4-methyl-2-pentanone (5.43 g, 30.3 mmol) 40 ml) of the mixture was heated at 150 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into 10% NaHCO ₃ solution, the mixture was extracted with toluene, dried (MgSO ₄₎ organic layer was filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc:EtOAc:EtOAc:EtOAc: Yield: 2.9 g of intermediate product 111 (52%).

B. Preparation of compounds Example B1 Preparation of Compound 1

Add Cs ₂ CO ₃ (0.56 g, 1.72 mmol), Pd ₂ (dba) ₃ (0.039 g, 0.043 mmol) and BINAP (0.053 g, 0.086 mmol) to intermediate 16 (0.25 g) , 0.859 mmol) and intermediate 2 (0.184 g, 0.902 mmol) of DMF (80 mL), the reaction mixture was flushed with N ₂ 5 minutes and then heated at 100 ℃ 18 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM, and the organic phase in H ₂ O, dried (MgSO _4), filtered and the solvent was evaporated in vacuo, the residue was purified by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID5 cm); mobile phase: (0.25% NH ₄ CO ₃ aq, MeOH + CH ₃ CN). The product fractions were collected and concentrated under reduced pressure. The residue was suspended in DIPE, and the precipitate was collected by filtration and dried at 60 ° C under vacuum. Yield: 0.068 g of compound (19%).

Example B2 Preparation of compound 2

Add Cs ₂ CO ₃ (0.616 g, 1.892 mmol), Pd ₂ (dba) ₃ (0.043 g, 0.047 mmol) and BINAP (0.058 g, 0.094 mmol) to intermediate containing 5 (0.3 g) , 0.95 mmol) and intermediate 2 (0.203 g, 0.993 mmol) of DMF (20 ml), and the mixture flushed with N ₂ 5 minutes and then heated at 100 ℃ 18 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM, and the organic phase in H ₂ O, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. Residue to purified preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ CO ₃ aq, MeOH + CH ₃ CN). The product fractions were collected and concentrated under reduced pressure. The solid product was dried under vacuum at 60 °C. Yield: 0.129 g of compound 2 (30%).

Example B3 Preparation of compound 3

Intermediate 16 (0.230 g, 0.793 mmol), Pd ₂ (dba) ₃ (0.060 g, 0.066 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.069 g, 0.145 mmol) and Cs ₂ CO ₃ (0.646 g, 1.98 mmol) were added to intermediate product 4 (0.135 g) A solution of 0.661 mmol of 2-methyl-2-propanol (10 mL) was taken and the mixture was warmed overnight at 110 °C. After cooling, H ₂ O was added and the product was extracted with DCM. Dried (MgSO ₄₎ organic phase was filtered and concentrated under reduced pressure. The residue was purified on a hydrazine gel by flash column chromatography (eluent: DCM / MeOH 100/0 to 98/2) and product fractions were collected and tested. The residue was crystallized from DIPE, filtered and dried at 80 ° C under vacuum. Yield: 0.032 g of compound 3 (11.7%).

Example B4 d) Preparation of compound 4

Will contain intermediate 7 (0.070 g, 0.14 mmol), 5-bromo-2-methylthiazole (0.051 g, 0.29 mmol), Cs ₂ CO ₃ (0.047 g, 0.14 mmol), Pd ( PPh ₃ ) ₄ (0.033 g, 0.29 mmol) and 3N aqueous NaOH (0.024 mL, 0.07 mmol) 1,4-two Dioxane (10 mL) was flushed with N _{2 2} min. The reaction mixture was stirred at 80 ° C overnight. After cooling, H ₂ O was added and the product was extracted with DCM. The organic phase was washed with brine, dried (Na ₂ SO _4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID5 cm); mobile phase: (0.25% NH ₄ CO _{3 aq, MeOH + CH 3 CN)]} . The product fractions were collected and concentrated under reduced pressure. Yield: 0.013 g of compound 4 (19.7%).

Example B5 Preparation of compound 5

Will contain intermediate 6 (0.220 g, 0.50 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-di Boran-2-yl)-1,3-thiazole (859833-13-9, 0.240 g, 1.0 mmol), Pd(PPh ₃ ) ₄ (0.116 g, 0.1 mmol), Cs ₂ CO ₃ ( 0.163 g, 0.50 mmol, and 3N NaOH aqueous solution (0.084 mL, 0.251 mmol) of 1,4-two Dioxane (20 ml) was flushed with N _{2 2} min. The reaction mixture was stirred at 80 ° C overnight. After cooling, the reaction mixture was concentrated, added H ₂ O, and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na ₂ SO ₄₎ filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 micron, 250 g, ID 5 cm); mobile phase: (0.5% NH ₄ OAc in water + 10% CH ₃ CN, CH ₃ CN)]. The product fractions were collected and concentrated under reduced pressure. Yield: 0.078 g of compound 5 (33%).

Example B6 Preparation of compound 6

Will contain intermediate product 6 (0.220 g, 0.502 mmol), Pd(PPh ₃ ) ₄ (0.116 g, 0.1 mmol) 1,4-two The alkane (20 mL) solution was flushed with N2 for ₂ min and the mixture was stirred at room temperature for 10 min. Add 1 H -pyridyl -1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-di Dioxaborolan-2-yl) (0.223 g, 1.0 mmol), and Cs ₂ CO ₃ (0.327 g, 1.0 mmol) to the reaction mixture. After stirring at room temperature for 10 minutes, aqueous 3N NaOH (0.084 mL, 0.21 m. Mixture was reacted at 80 ℃ was stirred overnight. After cooling, the reaction mixture was concentrated, added H ₂ O, and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na ₂ SO _4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 micron, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ CO ₃ aqueous solution, CH ₃ CN)]. The product fractions were collected and concentrated under reduced pressure. Yield: 0.055 g of compound 6 (24%).

Example B7 Preparation of Compound 7

Add Cs ₂ CO ₃ (1.137 g, 3.491 mmol), Pd ₂ (dba) ₃ (0.080 g, 0.087 mmol) and BINAP (0.109 g, 0.175 mmol) to intermediate 16 (0.508 g) , 1.75 mmol, and a solution of intermediate 9 (0.400 g, 1.83 mmol) in DMF (30 mL). The mixture was rinsed with N _{2 for} 5 minutes. The reaction mixture was then heated at 100 &lt;0&gt;C for 18 h then concentrated under reduced pressure. The residue was dissolved in DCM, and the organic phase was washed with H ₂ O, dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ CO _{3 aq, MeOH + CH 3 CN)]} . The product fractions were collected and evaporated, and the residue was purified eluting with EtOAc EtOAc EtOAc The product fractions were collected and the solvent was evaporated, the residue crystallised from n-heptane / DIPE, and the precipitate was filtered and dried at 50 ° C under vacuum. Yield: 0.099 g of compound 7 (13.2%).

Example B8 Preparation of compound 8

Add Cs ₂ CO ₃ (0.261 g, 0.80 mmol), Pd ₂ (dba) ₃ (0.018 g, 0.02 mmol) and BINAP (0.025 g, 0.04 mmol) to intermediate containing 21 (0.115 g) , 0.4 mmol) and intermediate 9 (0.091 g, 0.42 mmol) of DMF (20 ml), and the mixture was flushed with N ₂ 5 minutes. The reaction mixture was heated at 100 deg.] C for 18 hours and then concentrated under reduced pressure, the residue was dissolved in DCM and the organic phase was washed with H ₂ O, dried (MgSO _4), filtered, and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID5 cm); mobile phase: (0.25% NH ₄ CO _{3 aq, MeOH + CH 3 CN)]} . The product fractions were collected and concentrated under reduced pressure and the solid residue was dried at <RTIgt; Yield: 0.043 g of compound 8 (25.3%).

Example B9 Preparation of compound 9

Intermediate 19 (0.305 g, 1 mmol), Pd ₂ (dba) ₃ (0.091 g, 0.0.98 mmol), cyclohexyl [2', 4', 6'-tris (1-methyl) Ethyl)[1,1'-bisphenyl]-2-yl]phosphine (0.095 g, 0.2 mmol) and Cs ₂ CO ₃ (0.978 g, 3.0 mmol) were added to intermediate 13 (0.172). </ RTI></RTI></RTI></RTI></RTI><RTIgt;</RTI></RTI><RTIgt; the organic phase was washed with H ₂ O, dried (MgSO _4), filtered, and concentrated under reduced pressure. The residue was purified on silica gel chromatography to step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 98/2). The product fractions were collected and the solvent was evaporated, yield: 0.160 g of Compound 9 (37.4%).

Example B10 Preparation of Compound 10

Intermediate 19 (0.300 g, 0.983 mmol), Pd ₂ (dba) ₃ (0.090 g, 0.098 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.103 g, 0.216 mmol) and Cs ₂ CO ₃ (0.961 g, 2.95 mmol) were added to the intermediate containing 15 (0.172 g) A solution of 1 mmol of 2-methyl-2-propanol (10 mL) was obtained and the mixture was warmed overnight at 110 °C. After cooling, H ₂ O was added and the mixture was stirred for 10 min before diluted with DCM and filtered over Celite. The filtrate was washed with H ₂ O, and the organic phase was dried (MgSO _4), and concentrated under reduced pressure. The residue was purified by flash chromatography on hydrazine gel (eluent: DCM/MeOH 100/0 to 95/5). The product fractions were collected and the solvent was evaporated. Yield: 0.169 g of compound 10 (43%).

Example B11 Preparation of compound 11

Intermediate 20 (0.210 g, 0.684 mmol), Pd ₂ (dba) ₃ (0.062 g, 0.068 mmol), dicyclohexyl [2', 4', 6'-tri (1-methyl b) [1,1'-Bisyl]-2-yl]phosphine (0.071 g, 0.15 mmol) and Cs ₂ CO ₃ (0.688 g, 2.05 mmol) were added to intermediate containing 2 (0.139 g) A solution of 0.684 mmol of 2-methyl-2-propanol (10 mL) was taken and the mixture was stirred at 110 ° C for 6 h. After cooling, H ₂ O was added and the product was extracted with DCM. The organic phase was dried (MgSO ₄₎ and concentrated under reduced pressure, the residue was purified by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 micron, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ CO ₃ aqueous solution, CH ₃ CN)]. The product fractions were collected and concentrated under reduced pressure. Yield: 0.197 g of compound 11 (67%).

Example B12 Preparation of compound 12

Intermediate 19 (0.660 g, 2.16 mmol), Pd ₂ (dba) ₃ (0.198 g, 0.216 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.226 g, 0.476 mmol) and Cs ₂ CO ₃ (2.115 g, 6.49 mmol) were added to intermediate containing 2 (0.441 g) A solution of 2.16 mmol of 2-methyl-2-propanol (30 mL) was obtained. After cooling, the solvent was evaporated. H ₂ O was added and the mixture was extracted with DCM, the organic layer was separated, dried (MgSO ₄₎ and concentrated under reduced pressure. The residue was purified on silica gel chromatography to step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 99/1). The product fractions were collected and the solvent was evaporated and the product crystallised from DIPE, filtered and dried in vacuo. Yield: 0.465 g of compound 12 (50%).

Example B13 Preparation of compound 13

Intermediate 19 (0.304 g, 0.99 mmol), Pd ₂ (dba) ₃ (0.091 g, 0.099 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.104 g, 0.22 mmol) and Cs ₂ CO ₃ (0.976 g, 3.0 mmol) were added to intermediate product 26 (0.203 g) A solution of 1.0 mmol of 2-methyl-2-propanol (8 mL) was obtained and the reaction mixture was heated at 110 ° C for 16 h. After cooling, H ₂ O was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO ₄₎ and concentrated under reduced pressure. The residue was purified by flash chromatography on hydrazine gel (eluent: DCM without gradient). The product fractions were collected and the solvent was evaporated and the product crystallised from DIPE, filtered and dried in vacuo. Yield: 0.065 g of compound 13 (15.2%).

Example B14 Preparation of compound 14

Intermediate product 24 (0.298 g, 1.14 mmol), Pd ₂ (dba) ₃ (0.104 g, 0.114 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.108 g, 0.228 mmol) and Cs ₂ CO ₃ (1.108 g, 3.42 mmol) were added to intermediate 4 (0.233 g, A solution of 1.14 mmol of 2-methyl-2-propanol (15 mL) was taken and the mixture was warmed overnight. After cooling, H ₂ O was added and the product was extracted with DCM. Dried (MgSO ₄₎ organic phase was filtered and concentrated under reduced pressure. The residue was crystallized from DIPE / CN ₃ CN and filtered and dried in vacuo. Yield: 0.246 g of compound 14 (50%).

Example B15 Preparation of compound 15

Intermediate 34 (0.320 g, 0.96 mmol), Pd ₂ (dba) ₃ (0.088 g, 0.096 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.091 g, 0.192 mmol) and CS ₂ CO ₃ (0.939 g, 2.881 mmol) were added to intermediate 31 (0.320 g) A solution of 0.96 mmol of 2-methyl-2-propanol (15 mL) was obtained and the mixture was warmed overnight at 100 °C. After cooling, H ₂ O was added and the product was extracted with DCM. Dried (MgSO ₄₎ organic phase was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc:EtOAc The product fractions were collected and the solvent was evaporated, yield: 0.216 g of Compound 15 (51.5%).

Example B16 Preparation of Compound 16

Intermediate 19 (0.336 g, 1.10 mmol), Pd ₂ (dba) ₃ (0.101 g, 0.11 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.115 g, 0.242 mmol) and Cs ₂ CO ₃ (1.077 g, 3.31 mmol) were added to intermediate product 4 (0.225 g) In a solution of 1.10 mmoles of 2-methyl-2-propanol (15 mL), and the reaction mixture was heated at 90 ° C for 72 hours. After cooling, the solvent was evaporated, H ₂ O was added and the product was extracted with DCM. Dried (MgSO ₄₎ organic phase was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc: Dry at 80 ° C, yield: 0.220 g of compound 16 (46.6%).

Example B17 Preparation of compound 17

Intermediate 41 (0.22 g, 0.84 mmol), Pd ₂ (dba) ₃ (0.077 g, 0.084 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.080 g, 0.168 mmol) and Cs ₂ CO ₃ (0.822 g, 2.52 mmol) were added to intermediate 43 (0.161 g) , a solution of 0.841 mmol of 2-methyl-2-propanol (15 ml), and the reaction mixture was heated at 100 ° C for 20 hours. After cooling, the solvent was evaporated, add H ₂ O, and the product was extracted with DCM. The organic phase was dried (MgSO _4), filtered and the solvent was evaporated. The residue was purified on silica gel chromatography to step _{(eluent: DCM / MeOH (NH 3)} 99/1), parts of the product was filtered and collected, and the solvent was evaporated. Yield: 0.20 g of compound 17 (57%).

Example B18 Preparation of Compound 18

Intermediate 34 (0.190 g, 0.57 mmol), Pd ₂ (dba) ₃ (0.052 g, 0.057 mmol), dicyclohexyl [2', 4', 6'-tris (1-methyl b) [1,1'-bisphenyl]-2-yl]phosphine (0.054 g, 0.114 mmol) and Cs ₂ CO ₃ (0.558 g, 1.71 mmol) were added to intermediate product 48 (0.100 g) , a solution of 0.571 mmol of 2-methyl-2-propanol (10 mL), and the reaction mixture was heated at 110 ° C for 14 hours. After cooling, H ₂ O was added and the product was extracted with DCM. Dried (MgSO ₄₎ organic phase was filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography to step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 98/2). The product fractions were collected and the solvent was evaporated, yield: </RTI><RTIgt;

Example B19 Preparation of Compound 169

The intermediate product containing 90 (30 mg, 0.056 mmol) and Raney nickel was (20 mg) of THF (30 mL) was stirred under H ₂ gas (atmospheric pressure) at room temperature. After the draw H _{2 (2} equiv), the catalyst was filtered off over diatomaceous earth, the solvent was evaporated and the residue was partitioned between DCM and H ₂ O, the organic layer was dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC [RP Vydac Denali C18 (10 [mu] m, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ CO ₃ aq, CH ₃ CN)]. The product fractions were collected and concentrated under reduced pressure. Yield: 1.1 mg of compound 169 (4%).

Example B20 Preparation of Compound 188

Intermediate 57 (0.224 g, 1.15 mmol), Pd(OAc) ₂ (0.034 g, 0.15 mmol), Xantphos (0.133 g, 0.23 mmol) and Cs ₂ CO ₃ (0.498 g, 1.53 m) Mohr) added to intermediate product 63 (0.185 g, 0.76 mmol) A solution of the alkane (3 mL) was obtained and the reaction mixture was heated at 160 ° C for 1 hour under microwave irradiation. After cooling, H ₂ O and the product was extracted with DCM, dried (MgSO ₄₎ organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ CO ₃ aq, MeOH)]. The product fractions were collected and concentrated under reduced pressure. Yield: 0.040 g of compound 188 (13%).

Example B21 Preparation of Compound 128

Intermediate 34 (0.405 g, 1.17 mmol), Pd ₂ (dba) ₃ (0.107 g, 0.12 mmol), X-Phos (0.122 g, 0.26 mmol) and Cs ₂ CO ₃ (1.14 g) A solution of intermediate product 56 (0.250 g, 1.17 mmol) in 2-methyl-2-propanol (10 mL) was then taken and the mixture was warmed at 100 &lt;0&gt;C for 4 h. After cooling, H ₂ O was added and the product was extracted with DCM. Dried (MgSO ₄₎ organic phase was filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography to step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 98/2). The product fractions were collected and the solvent was evaporated and the residue was crystallised from DIPE/2-propanol. Yield: 0.284 g of compound 128 (52%).

Example B22 Preparation of Compound 165

Containing compound 143 (according to Example B3, and the intermediate 98 was prepared from the intermediates 2, 150 mg, 0.33 mmol) of THF (5 ml) was slowly added at 0 ℃ 1M CH ₃ Li to a solution of THF ( 1 ml, 1 mmol) solution, the mixture was stirred at room temperature for 2 hours, then an additional 1 M CH ₃ Li in THF (1 mL, 1 mmol) was added and stirred at room temperature for 1 hour. 10% aq. HCl and the mixture was extracted with DCM. Dried (MgSO ₄₎ organic phase was filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography to step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 99/1). The product fractions were collected and the solvent was evaporated, yield: 21 mg of Compound 165 (15%).

Example B23 Preparation of compound 120

And Raney nickel was (20 mg) of MeOH containing compound 123 (B18, prepared according to Example 104 by the intermediate and intermediate 2, 40 mg, 0.088 mmol) (NH ₃₎ (40 ml) in H ₂ Stir under (atmospheric pressure) at room temperature. After suction H (2 eq) ₂ on kieselguhr catalyst was filtered off, the solvent was evaporated, and the residue was chromatographed on silica gel purification step (eluent _{to: DCM / MeOH (NH 3)} 90 / 10). The product fractions were collected and the solvent was evaporated. Yield: 7 mg of compound 120 (17%).

Example B24 Preparation of Compound 197

A mixture of 1:1 THF and MeOH (100 mL) was added to Pd/C (10%, 500 mg) under N ₂ atmosphere, then DIPE (0.5 mL) containing 0.4% thiophene solution, Compound 198 ( prepared according to Example B3, 49 mg, 0.11 mmol) and KOAc (13 mg, 0.13 mmol), and the reaction mixture was stirred under H ₂ at 25 deg.] C at atmospheric pressure until 1 equivalent of H ₂ absorption. The catalyst was filtered off, the filtrate was evaporated on a diatomaceous earth, and the residue was distributed between DCM and saturated aqueous NaHCO _3. Dried (MgSO ₄₎ organic layer was filtered and the solvent was evaporated, the residue was purified on a silica quenched to a gel chromatography _{(eluent: DCM / MeOH (NH 3)} 100/0 to 96/4). The product fractions were collected and the solvent was evaporated, yield: 9.5 mg of Compound 197 (21%).

Example B25 Preparation of Compound 179

Will contain 4-(2-methyl- Zin-5-yl)-phenylamine (615 mg, 3.53 mmol), intermediate 101 (933 mg, 3.21 mmol), and DIPEA (1.24 g, 9.62 mmol) CH ₃ CN (10) The mixture was heated at 200 ° C for 1.5 hours under microwave irradiation. And the volatiles were evaporated under reduced pressure, and the residue was partitioned between DCM and H ₂ O, the organic layer was dried (MgSO _4), filtered and the solvent was evaporated. The residue was purified on silica gel chromatography to step _{(eluent: DCM / MeOH (NH 3)} 95/5). The fractions containing the product were collected and the solvent was evaporated. The residue was further purified by preparative HPLC [RP Shandon Hyperprep C18 BDS (8 [mu] m, 250 g, ID 5 cm); mobile phase: (0.25% NH ₄ CO ₃ aq, MeOH)]. The product fractions were collected and concentrated under reduced pressure. Yield: 0.031 g of compound 179 (3%).

Example B26 a) Preparation of compound 185

1-Iodo-2,5-pyrrolidone (837 mg, 3.72 mmol) was added to DCM (50 mL) and AcOH (5 mL) containing compound 42 (1.3 g, 3.38 mmol). the mixture was stirred at room temperature for 5 minutes and then washed with aqueous NaHCO _3, dried (MgSO ₄₎ organic layer was filtered and concentrated in vacuo. The residue was purified on silica gel chromatography to step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 97/3), parts of the product was collected by filtration and the solvent was evaporated. Yield: 500 mg of compound 185 (29%).

b) Preparation of compound 177

Adding isopropenylboronic acid pinacol ester (151 mg, 0.9 mmol) and Pd(PPh ₃ ) ₄ (52 mg, 0.045 mmol) to compound 185 (230 mg, 0.45 mmol) Dioxane (2 mL) and aqueous NaHCO ₃ (2 mL) was added, and the mixture was stirred and heated under microwave irradiation at 150 ℃ 10 min. The reaction mixture was cooled to room rt and filtered over EtOAc over EtOAc. The residue was purified on a silica gel column chromatography in step _{(eluent: DCM / MeOH (NH 3)} 100/0 to 97/3). The product fractions were collected and the solvent was evaporated, yield: 14 mg of Compound 177 (7%).

c) Preparation of Compound 175

The MeOH (40 mL) was added under N ₂ pressure to Pt / C 5% (50 mg), followed by addition of compound 177 (150 mg, 0.35 mmol). The reaction mixture was stirred at 25 ° C under a pressure of H ₂ until 1 equivalent of H _{2 was taken} . The catalyst was filtered off on celite and the filtrate was evaporated. Yield: 70 mg of crude compound 175 (46%).

Example B27 a) Preparation of compound 156

A solution of 3M CH ₃ MgBr in Et ₂ O was added at 0 ° C to a solution of compound 151 (prepared from intermediate 2 and intermediate 111, 105 mg, 0.26 mmol) in THF (20 mL) . The reaction mixture was stirred at room temperature overnight, then saturated aqueous NH ₄ Cl quench, water was added, and the mixture was extracted with DCM. The organic layer was dried (MgSO _4), filtered, concentrated in vacuo, the residue was purified by chromatography in step (eluent: DCM / MeOH 100/0 to 95/5) on silica gel. The product was collected by filtration and the solvent component was evaporated, the residue was dissolved in DIPE / CH ₃ CN, and the added 6N HCl containing 2-propanol solution, the resulting precipitate was collected by filtration and dried. Yield: 3.2 mg of compound 156 HCl salt (3%).

b) Preparation of compound 162

A solution of NaOH (2 g, 50 mmol) in H ₂ O (40 mL) was added to compound 151 (0.4 g, 1 mmol) Alkane (40 mL) solution. The reaction mixture was stirred at reflux for 3 h then cooled to rt and neutralized to pH 7 with concentrated aqueous HCI. The resulting precipitate was collected by filtration and dried. A portion of the residue (213 mg, 0.51 mmol) was dissolved in DCM (EtOAc) (EtOAc) The reaction mixture was stirred at rt EtOAc then EtOAc (EtOAc) The mixture was partitioned between DCM and saturated aqueous NaHCO _3, the organic layer was dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on hydrazine gel (eluent: DCM/MeOH 100/0 to 95/5). The product fractions were collected and the solvent was evaporated and the residue was crystallised from DIPE. Yield: 58 mg of compound 162 (20% of 2 steps).

Compounds 1 to 202 in Tables 1, 2, 3, 4 and 5 list compounds prepared in a manner similar to one of the above examples. If no salt form is indicated, the compound is obtained as the free base. 'Pr.' denotes the number of the examples according to the protocol synthesized by the compound. 'Co. No.' means the compound number. 'Bx' indicates the general experimental procedure 1 using sodium t-butoxide, toluene, BINAP and Pd(OAc) ₂ .

In order to obtain the HCl salt form of the compound, a general procedure known to those skilled in the art can be used. In the general procedure, for example, the crude residue (free base) was dissolved in DIPE or Et ₂ O, followed by the dropwise addition of 2-propanol containing a solution of 6N HCl containing Et 1N HCl solution or the ₂ O. The mixture was stirred for 10 minutes and the product was filtered and dried EtOAc EtOAc.

Analysis section LCMS Normal procedure A

Acquity UPLC (including a secondary pump with a degasser, a sampler, a column heater (set at 55 °C), a two-pole array detector (DAD), and a specific column of the following methods) The Waters) system performs LC measurements. The stream from the column is split to the MS spectrometer, which is equipped with an electrospray ionization source. The mass spectrum was obtained by scanning 100 to 1000 in 0.18 seconds using a residence time of 0.02 seconds, the capillary needle voltage was 3.5 kV, and the source temperature was maintained at 140 °C. Data was obtained using a Waters-Micromass MassLynx-Openlynx data system using nitrogen as the nebulizer gas.

Normal procedure B

HPLC measurements were taken using an Agilent 1100 Series containing a secondary pump with degasser, autosampler, column oven, UV detector and the following specific methods. The flow from the column was shunted. To the MS spectrometer, the MS detector is equipped with an electrospray ionization source. The capillary voltage was 3.5 kV, the quaternary temperature was measured at 100 ° C and the desolvation temperature was 300 ° C. Using nitrogen as the nebulizer gas, the data was obtained using an Agilent Chemstation data system.

Normal procedure C

Use a four-stage pump with a degasser, an automatic sampler, a column oven (set at 40 ° C unless otherwise noted), a two-pole array detector (DAD), and the following individual methods HPLC analysis of the column's Alliance HT 2790 (Waters) system. The stream from the column is split to the MS spectrometer, which is equipped with an electrospray ionization source. The mass spectrum was obtained by scanning 100 to 1000 in 1 second using a residence time of 0.1 second, the capillary needle voltage was 3 kV, and the source temperature was maintained at 140 °C. Data was obtained using a Waters-Micromass MassLynx-Openlynx data system using nitrogen as the nebulizer gas.

LCMS Method 1

In addition to the usual procedure A: reverse phase UPLC (Ultra-Performance Liquid Chromatography) was carried out on a bridged ethyloxane/ceria mixed (BEH) C18 column (1.7 micron, 2.1 x 50 mm; Waters Acquity) at a flow rate of 0.8. ML/min. Using two mobile phases (H ₂ O/CH ₃ CN 95/5 containing 25 mM NH ₄ Oac; mobile phase B: CH ₃ CN) was carried out in 1.3 minutes from 95% A and 5% B to 5% A with Gradient conditions of 95% B and maintained for 0.3 minutes. The injection volume of 0..5 μl was used, and the cone voltage for the positive ionization mode was 10 V, and the negative ionization mode was 20 V.

LCMS Method 2

Except for the usual procedure A: reverse phase UPLC was carried out on a BEH C18 column (1.7 micron, 2.1 x 50 mm; Waters Acquity) at a flow rate of 0.8 ml/min. Using two mobile phases (mobile phase A: H ₂ O/MeOH 95/5 with 0.1% formic acid; mobile phase B: MeOH) was carried out in 1.3 minutes from 95% A and 5% B to 5% A and 95% The gradient condition of B was maintained for 0.2 minutes. Using a 0.5 microliter injection volume, the taper voltage for positive ionization mode is 10V and the negative ionization mode is 20V.

LCMS Method 3

Except for the usual procedure B: reverse phase HPLC was carried out on a YMC-Pack ODS-AQC18 column (4.6 x 50 mm) at a flow rate of 2.6 ml/min. Using 95% water and 5% CH ₃ CN to 95% CH ₃ CN gradient of 4.80 minutes, 1.20 minutes and maintained. Mass spectra were obtained via a scan of 100 to 1000 with an injection volume of 10 microliters and a column temperature of 35 °C.

LCMS Method 4

Except for the usual procedure C: column heater was set at 60 ° C, reverse phase HPLC was performed on a Xterra MS C18 column (3.5 micron, 4.6 x 100 mm) at a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM NH ₄ OAc + 5% CH ₃ CN; mobile phase B: CH ₃ CN; mobile phase C: MeOH) were used, from 100% A to 50% B in 6.5 minutes And 50% C, to 100% B for 0.5 minute gradient conditions, and maintain this condition for 1 minute and re-equilibrate at 100% A for 1.5 minutes. Using a 10 microliter injection volume, the cone voltage for positive ionization mode is 10V and the negative ionization mode is 20V.

LCMS Method 5

Except for the usual procedure C: column heater was set at 45 ° C, reverse phase HPLC was performed on an Atlantis C18 column (3.5 micron, 4.6 x 100 mm) at a flow rate of 1.6 ml/min. Two mobile phases (mobile phase A: 70% MeOH + 30% H ₂ O; mobile phase B: H ₂ O / MeOH 95/5 with 0.1% formic acid) were used, from 100% B to 5% in 9 minutes Gradient conditions of B + 95% A and maintained for 3 minutes. Using a 10 microliter injection volume, the cone voltage for positive ionization mode is 10V and the negative ionization mode is 20V.

LCMS Method 6

Except for the usual procedure C: column heater was set at 60 ° C, reverse phase HPLC was performed on a Xterra MS C18 column (3.5 micron, 4.6 x 100 mm) at a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM NH ₄ OAc + 5% CH ₃ CN; mobile phase B: CH ₃ CN; mobile phase C: MeOH) were used, from 100% A to 1% in 6.5 minutes A, 49% B and 50% C, to 1% A and 99% B 1 minute gradient conditions, and maintained for 1 minute and re-equilibrated at 100% A for 1.5 minutes. Using a 10 microliter injection volume, the cone voltage for positive ionization mode is 10V and the negative ionization mode is 20V.

LCMS Method 7

Except for the usual procedure A: reverse phase UPLC was carried out on a BEH C18 column (1.7 micron, 2.1 x 50 mm; Waters Acquity) at a flow rate of 0.8 ml/min. Using two mobile phases (mobile phase A: H ₂ O/CH ₃ CN 95/5 with 25 mM NH ₄ Oac; mobile phase B: CH ₃ CN) was carried out from 95% A and 5% B in 1.3 minutes Gradient conditions of 5% A and 95% B, and maintained for 0.3 minutes. Using a 0.5 microliter injection volume, the cone voltage for the positive ionization mode is 30V, and the negative ionization mode is 30V.

Melting point

For many compounds, the melting point (m.p.) is determined by DSC823e (Mettler-Toledo). The melting point was measured at a temperature gradient of 30 ° C / min, the maximum temperature was 400 ° C, and the value was the peak.

The results of the analytical measurements are shown in Table 6.

NMR

For some compounds, ¹ H NMR spectra were recorded on a Bruker DPX-360 with standard pulse sequence, on a Bruker DPX-400, or on a Bruker Avance 600 spectrometer, each operating at 360, 400 and 600 MHz using CHLOROFORM- d or DMSO- d _{6 is} used as a solvent. The chemical shift (δ) is described as parts per million (ppm) relative to tetramethyl decane (TMS), which is used as an internal standard.

Compound 1: ¹ H NMR (360 MHz, DMSO- d ₆ ) δ ppm 2.11 (s, 3 H), 3.80 (s, 3 H), 6.81 (t, J = 7.1 Hz, 1 H), 7.03-7.13 (m) , 2 H), 7.18 (d, J = 2.0 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 7.30 (t, J = 8.7 Hz, 2 H), 8.02-8.11 (m, 3 H), 8.27 (s, 1 H), 8.39 (s, 1 H), 8.52 (s, 1 H).

Compound 2: ¹ H NMR (360 MHz, DMSO- d ₆ ) δ ppm 2.11 (s, 3 H), 2.65 (s, 3 H), 3.80 (s, 3 H), 3.83 (s, 3 H), 6.88 ( t, J = 7.1 Hz, 1 H), 6.94 (dt, J = 5.9,2.9 Hz, 1 H), 7.05-7.11 (m, 2 H), 7.17 (d, J = 2.0 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 1 H), 7.37-7.43 (m, 3 H), 7.90 (d, J = 6.8 Hz, 1 H), 8.26 (s, 1 H), 8.53 (s, 1 H) .

Compound ^{3: 1 H NMR (360 MHz} , DMSO- d 6) δppm 2.46 (s, 3 H), 3.92 (s, 3 H), 6.82 (t, J = 7.1 Hz, 1 H), 7.06 (d, J = 7.5 Hz, 1 H), 7.09 (dd, J = 8.5, 2.0 Hz, 1 H), 7.19 (d, J = 2.0 Hz, 1 H), 7.24 (s, 1 H), 7.30 (t, J = 8.8 Hz, 2 H), 7.56 (d, J = 8.4 Hz, 1 H), 8.04-8.09 (m, 3 H), 8.39 (s, 1 H), 8.48 (s, 1 H).

Compound 4: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.64 (s, 3 H), 2.65 (s, 3 H), 3.83 (s, 3 H), 3.89 (s, 3 H), 6.87 ( t, J = 7.1 Hz, 1 H), 6.94 (dt, J = 6.4, 2.8 Hz, 1 H), 7.04-7.09 (m, 2 H), 7.18 (d, J = 2.2 Hz, 1 H), 7.36 -7.44 (m, 3 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.88 (d, J = 6.7 Hz, 1 H), 7.97 (s, 1 H), 8.45 (s, 1 H) .

Compound 5: ¹ H NMR (360 MHz, DMSO- d ₆ ) δ ppm 2.22 (s, 3 H), 2.60 (s, 3 H), 2.65 (s, 3 H), 3.77 (s, 3 H), 3.83 ( s, 3 H), 6.87 (t, J = 7.1 Hz, 1 H), 6.94 (dt, J = 5.9, 3.0 Hz, 1 H), 7.03-7.10 (m, 2 H), 7.16 (d, J = 2.0 Hz, 1 H), 7.20 (d, J = 8.3 Hz, 1 H), 7.37-7.43 (m, 3 H), 7.88 (d, J = 6.8 Hz, 1 H), 8.46 (s, 1 H) .

Compound 6: ¹ H NMR (360 MHz, DMSO- d ₆ ) δ ppm 2.14 (s, 3 H), 2.64 (s, 3 H), 3.77 (s, 3 H), 3.78 (s, 3 H), 3.83 ( s, 3 H), 6.85 (t, J = 7.1 Hz, 1 H), 6.94 (dt, J = 6.0, 2.9 Hz, 1 H), 7.00 (d, J = 7.5 Hz, 1 H), 7.00-7.04 (m, 1 H), 7.12 (d, J = 2.1 Hz, 1 H), 7.16 (d, J = 8.2 Hz, 1 H), 7.38-7.42 (m, 3 H), 7.65 (s, 1 H) , 7.83 (d, J = 6.7 Hz, 1 H), 8.25 (s, 1 H).

Compound ^{7: 1 H NMR (360 MHz} , DMSO- d 6) δppm 2.04 (s, 3 H) 2.38 (s, 3 H) 3.80 (s, 3 H) 6.81 (t, J = 7.32 Hz, 1 H) 6.99 -7.11(m,2H) 7.16(d, J =1.83 Hz,1H) 7.24(d, J =8.42 Hz,1 H) 7.30(t, J =8.78 Hz, 2H) 7.99-8.15(m,3 H 8.39(s,1 H)8.48(s,1 H).

Compound ^{8: 1 H NMR (360 MHz} , DMSO- d 6) δppm 2.04 (s, 3 H), 2.38 (s, 3 H), 2.65 (s, 3 H), 3.79 (s, 3 H), 6.88 ( t, J = 7.1 Hz, 1 H), 7.04-7.11 (m, 2 H), 7.16 (d, J = 2.0 Hz, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.36 (t , J = 7.4 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 2 H), 7.86 (d, J = 7.7 Hz, 2 H), 7.89 (d, J = 6.7 Hz, 1 H), 8.48 (s, 1 H).

Compound 9: 1H NMR (360 MHz, CHLOROFORM- d ) δ ppm 3.76 (s, 3H), 3.81 (s, 3 H), 3.85 (s, 3 H), 6.24 (d, J = 1.9 Hz, 1 H), 6.92 (d, J = 2.1 Hz, 1 H), 6.94-7.01 (m, 2 H), 7.14 (s, 1 H), 7.17 (d, J = 8.2 Hz, 1 H), 7.22-7.32 (m, 4 H), 7.52 (d, J = 1.9 Hz, 1 H), 7.75 (dd, J = 8.5, 5.4 Hz, 2 H).

Compound 10: ¹ H NMR (360 MHz, DMSO- d ₆ ) δ ppm 2.35 (s, 3 H), 3.86 (s, 3 H), 7.21. (dd, J = 8.1, 1.4 Hz, 1 H), 7.25 (t , J = 7.8 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 1 H), 7.44 (t, J = 8.8 Hz, 2 H), 7.81 (dd, J = 8.8, 2.5 Hz, 1 H) , 7.94 (dd, J = 8.6, 5.6 Hz, 2 H), 8.28 (dd, J = 7.5, 1.3 Hz, 1 H), 8.32 (s, 1 H), 8.47 (d, J = 2.5 Hz, 1 H ), 9.22 (s, 1 H).

Compound 11: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 2.24 (s, 3 H), 2.76-2.90 (m, 2 H), 3.10-3.16 (m, 2 H), 3.76 (s, 3 H) , 3.85 (s, 3 H), 6.87-6.91 (m, 2 H), 6.97 (dd, J = 8.3, 2.1 Hz, 1 H), 6.96 (s, 1 H), 7.20 (t, J = 7.7 Hz) , 1 H), 7.24 (dd, J = 7.9, 1.5 HZ, 1 H), 7.85 (s, 1 H).

Compound ^{12: 1 H NMR (360 MHz} , DMSO- d 6) δppm 2.10 (s, 3 H), 3.75 (s, 3 H), 3.86 (s, 3 H), 6.95 (dd, J = 8.4,2.0 Hz , 1 H), 7.06 (d , J = 2.0 Hz, 1 H), 7.15-7.26 (m, 4 H), 7.43 (t, J = 8.7 Hz, 2 H), 7.92 (dd, J = 8.4,5.4 Hz, 2 H), 8.23 (s, 1 H), 8.53 (s, 1 H).

Compound 13: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 3.84 (s, 3 H), 3.89 (s, 3 H), 3.94 (s, 3 H), 6.89-6.93 (m, 2 H), 6.97 (dd, J = 8.2, 2.1 Hz, 1 H), 7.07 (s, 1 H), 7.21-7.28 (m, 4 H), 7.45 (d, J = 8.2 Hz, 1 H), 7.75 (dd, J = 8.6, 5.3 Hz, 2 H), 7.79 (s, 1 H), 7.83 (s, 1 H).

Compound 14: ¹ H NMR (360 MHz, DMsO- d ₆ ) δ ppm 2.46 (s, 3 H), 3.86 (s, 3 H), 3.92 (s, 3 H), 7.18 (d, J = 5.8 Hz, 1 H), 7.23 (s, 1 H), 7.46 (t, J = 8.8 Hz, 2 H), 7.53 (d, J = 9.0 Hz, 1 H), 7.93-7.99 (m, 4 H), 8.03 ( d, J = 5.8 Hz, 1 H), 9.26 (s, 1 H).

Compound ^{15: 1 H NMR (360 MHz} , DMsO- d 6) δppm 1.59 (d, J = 6.9 Hz, 6 H), 2.47 (s, 3 H), 4.58-4.69 (m, 1 H), 7.20 (t , J = 8.1 Hz, 1 H), 7.35 (d, J = 8.8 Hz, 1 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.39 (s, 1 H), 7.43 (t, J = 8.8 Hz, 2 H), 7.74 (dd, J = 8.6, 5.5 Hz, 2 H), 7.83 (dd, J = 8.8, 2.5 Hz, 1 H), 8.24 (d, J = 8.0 Hz, 1 H), 8.52 (d, J = 2.4 Hz, 1 H), 9.14 (s, 1 H).

Compound 16: ^J H NMR (360 MHz, DMsO- d ₆ ) δ ppm 2.45 (s, 3 H), 3.86 (s, 3 H), 3.86 (s, 3 H), 6.97 (dd, J = 8.5, 2.0 Hz , 1 H), 7.07 (d, J = 2.0 Hz, 1 H), 7.14 - 7.25 (m, 4 H), 7.43 (t, J = 8.8 Hz, 2 H), 7.49 (d, J = 8.5 Hz, 1 H), 7.92 (dd, J = 8.6, 5.5 Hz, 2 H), 8.50 (s, 1 H).

Compound ^{18: 1 H NMR (360 MHz} , CHLOROFORM- d) δppm 1.66 (d, J = 6.95 Hz, 6 H) 2.56 (s, 3 H) 4.73 (spt, J = 6.92,6.77 Hz, 1 H) 7.13 ( s, 1 H) 7.15-7.22 (m, 3 H) 7.22-7.28 (m, 2 H) 7.40 (s, 1 H) 7.54 (d, J = 8.78 Hz, 1 H) 7.62 (dd, J = 8.60, 5.31 Hz, 2 H) 7.69 (dd, J = 8.60, 2.74 Hz, 1 H) 8.61 (d, J = 2.56 Hz, 1 H).

Compound ^{25: 1 H NMR (360 MHz} , DMSO- d 6) δppm 1.68 (d, J = 6.95 Hz, 6 H) 2.47 (s, 3 H) 3.90 (s, 3 H) 4.71-4.82 (m, 1 H 6.93 (dd, J = 8.42, 1.83 Hz, 1 H) 6.98 (s, 1 H) 7.44 - 7.52 (m, 2 H) 7.57 (d, J = 8.42 Hz, 1 H) 7.61 (t, J = 8.96) Hz, 2 H) 7.67 (t, 1 H) 7.95 (dd, J = 8.60, 5.31 Hz, 2 H) 9.17 (br. s., 1 H).

Compound 38: ¹ H NMR (360 MHz, DMSO- d ₆ ) δ ppm 3.93 (s, 3 H) 6.82 (t, J = 7.32 Hz, 1 H) 7.08 (d, J = 7.68 Hz, 1 H) 7.11 (dd , J = 8.42, 2.20 Hz, 1 H) 7.21 (d, J = 2.20 Hz, 1 H) 7.30 (t, J = 8.78 Hz, 2 H) 7.40 (s, 1 H) 7.63 (d, J = 8.42 Hz) , 1 H) 8.01-8.09 (m, 3 H) 8.36 (s, 1 H) 8.40 (s, 1 H) 8.54 (s, 1 H).

Compound ^{40: 1 H NMR (360 MHz} , CHLOROFORM- d) δppm 2.49 (s, 3 H) 2.53 (s, 3 H) 3.88 (s, 3 H) 6.72 (dd, J = 7.32,6.95 Hz, 1 H) 6.85 (dd, J = 8.42, 2.93 Hz, 1 H) 6.94 (d, J = 6.95 Hz, 1 H) 7.14 (s, 1 H) 7.20 (d, J = 8.42 Hz, 1 H) 7.33 - 7.39 (m , 3 H) 7.51 (d, J = 2.56 Hz, 1 H) 7.60 (m, 2 H) 7.69 (s, 1 H) 7.71 (dd, J = 6.59,0.73 Hz, 1 H).

Compound ^{57: 1 H NMR (600 MHz} , CHLOROFORM- d) δppm 2.53 (s, 3 H), 2.53 (s, 3 H), 7.00-7.04 (m, 2 H), 7.15 (s, 1 H), 7.50 (d, J = 4.6 Hz, 1 H), 7.60 (d, J = 4.6 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 2 H), 7.62 (s, 1 H), 7.77 (dd, J = 8.1, 6.0 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 2 H), 8.20 (s, 1 H).

Compound 60: ¹ H NMR (600 MHz, CHLOROFORM- d ) δ ppm 2.52 (s, 3 H), 2.53 (s, 3 H), 6.99-7.05 (m, 2 H), 7.16 (s, 1 H), 7.59 (s, 1 H), 7.64 (d, J = 8.5 Hz, 2 H), 7.74 (d, J = 7.2 Hz, 1 H), 7.76 (s, 1 H), 7.93 (d, J = 8.6 Hz, 2 H), 8.24 (s, 1 H).

Compound ^{89: 1 H NMR (360 MHz} , DMSO- d 6) δppm 1.64 (d, J = 6.95 Hz, 6 H) 2.52 (s, 3 H) 4.72 (spt, 1 H) 7.18 (dd, J = 11.89, 1.65 Hz, 1 H) 7.52-7.64 (m, 4 H) 7.73 (d, J = 8.78 Hz, 1 H) 7.87-7.94 (m, 3 H) 8.60 (d, J = 2.56 Hz, 1 H) 9.74 ( Br. s.,1 H).

Compound 95: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 2.52 (s, 3 H) 3.80 (s, 3 H) 3.89 (s, 3 H) 3.94 (s, 3 H) 6.39 (d, J = 1.83) Hz, 1 H) 6.87-6.93 (m, 2 H) 7.00 (dd, J = 8.42, 2.20 Hz, 1 H) 7.10 (s, 1 H) 7.19-7.28 (m, 2 H) 7.29 (s, 1 H ) 7.66 (d, J = 8.42 Hz, 1 H) 7.72 (dd, J = 8.60, 5.31 Hz, 2 H).

Compound ^{97: 1 H NMR (360 MHz} , DMSO- d 6) δppm 2.46 (s, 3 H) 2.54 (s, 3 H) 3.83 (s, 3 H) 3.86 (s, 3 H) 3.94 (s, 3 H ) 7.02 (s, 1 H) 7.11-7.17 (m, 1 H) 7.22 (s, 1 H) 7.40-7.46 (m, 2 H) 7.46-7.54 (m, 2 H) 7.77 (dd, J = 8.78, 1.83 Hz, 1 H) 8.32 (d, J = 1.83 Hz, 1 H) 9.24 (s, 1 H).

Compound 99: ¹ H NMR (600 MHz, CHLOROFORM- d ) δ ppm 2.53 (s, 3 H), 2.66 (s, 3 H), 4.03 (s, 3 H), 7.12 (br. s., 1 H), 7.15 (s, 1 H), 7.19 (s, 1 H), 7.36 (d, J = 8.5 Hz, 2 H), 7.36 (s, 1 H), 7.62 (d, J = 8.5 Hz, 2 H), 8.00 (s, 1 H).

Compound 101: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 2.57 (s, 3 H) 3.91 (s, 3 H) 7.22 (s, 1 H) 7.24-7.33 (m, 2 H) 7.36 (s, 1 H) 7.45 (s, 1 H ) 7.61 (d, J = 8.78 Hz, 1 H) 7.71 (dd, J = 8.78,2.93 Hz, 1 H) 7.77 (dd, J = 8.78,5.12 Hz, 2 H) 8.64 (d, J = 2.56 Hz, 1 H).

Compound 106: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 2.57 (s, 3 H) 3.81 (s, 3 H) 6.65 (dd, J = 8.78, 1.83 Hz, 1 H) 6.90 (dd, J = 12.08) , 2.20 Hz, 1 H) 7.19 (s, 1 H) 7.25 (t, J = 8.23 Hz, 2 H) 7.44 (s, 1 H) 7.58 (d, J = 8.78 Hz, 1 H) 7.71-7.78 (m , 3 H) 8.60 (d, J = 2.56 Hz, 1 H).

Compound 127: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.49 (s, 3 H) 2.54 (s, 3 H) 3.81 (s, 3 H) 3.84 (s, 3 H) 7.00 (s, 1 H ) 7.31 (d, J = 8.48 Hz, 1 H) 7.34 (dd, J = 5.05, 1.41 Hz, 1 H) 7.40 (s, 1 H) 7.43 (t, J = 8.88 Hz, 2 H) 7.79 (dd, J = 8.48, 2.02 Hz, 1 H) 7.94 (dd, J = 8.88, 5.65 Hz, 2 H) 8.29 (d, J = 2.02 Hz, 1 H) 8.39 (d, J = 5.25 Hz, 1 H) 9.19 ( s, 1 H).

Compound 129: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 2.60 (s, 3 H) 3.85 (s, 3 H) 4.10 (s, 3 H) 6.65 (d, J = 8.05 Hz, 1 H) 7.02 ( d, J = 8.05 Hz, 1 H) 7.22-7.30 (m, 2 H) 7.30-7.37 (m, 2 H) 7.39 (s, 1 H) 7.62 (d, J = 8.42 Hz, 1 H) 7.76 (dd , J = 8.60, 5.31 Hz, 2 H) 7.91 (s, 1 H) 8.25 (d, J = 7.68 Hz, 1 H) 8.48 (d, J = 5.12 Hz, 1 H).

Compound 139: ¹ H NMR (360 MHz, DMSO- d ₆ ) δ ppm 2.48 (s, 3 H) 3.76 (s, 3 H) 3.86 (s, 3 H) 6.98 (dd, J = 8.42, 2.20 Hz, 1 H ) 7.08 (d, J = 2.20 Hz, 1 H) 7.12 - 7.34 (m, 5 H) 7.37 (s, 1 H) 7.44 (t, J = 8.78 Hz, 2 H) 7.93 (dd, J = 8.78, 5.49) Hz, 2 H) 8.38 (d, J = 5.12 Hz, 1 H) 8.50 (s, 1 H).

Compound 157: ¹ H NMR (360 MHz, DMSO- d ₆ ) δ ppm 0.96 (d, J = 6.59 Hz, 6 H) 2.12 (s, 3 H) 2.13 - 2.22 (m, 1 H) 2.73 (d, J = 6.95 Hz, 2 H) 3.81 (s, 3 H) 7.05 (dd, J = 8.42, 1.83 Hz, 1 H) 7.09 (d, J = 1.83 Hz, 1 H) 7.38 (d, J = 8.42 Hz, 1 H ) 7.55 (d, J = 10.98 Hz, 1 H) 8.06 (s, 1 H) 8.30 (s, 1 H) 8.56 (br.s., 1 H) 9.73 (br.s., 1 H).

Compound 167: ¹ H NMR (360 MHz, DMSO- d ₆ ) δ ppm 2.30 (s, 3 H) 2.49 (s, 3 H) 6.91 (t, J = 6.95 Hz, 1 H) 7.03 (d, J = 7.32 Hz , 1 H) 7.46 (s, 1 H) 7.54 (d, J = 7.32 Hz, 1 H) 7.60 (d, J = 8.78 Hz, 1 H) 7.68 (t, J = 7.68 Hz, 1 H) 7.76 (t , J = 7.68 Hz, 1 H) 7.81 (dd, J = 8.78, 2.56 Hz, 1 H) 7.85-7.93 (m, 2 H) 8.65 (d, J = 2.56 Hz, 1 H) 8.77 (s, 1 H ).

Compound 173: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 2.44 (s, 3 H) 2.57 (s, 3 H) 6.82 (t, J = 7.14 Hz, 1 H) 6.95 (d, J = 6.95 Hz, 1 H) 7.31 - 7.42 (m, 3 H) 7.44 (s, 1 H) 7.48 - 7.62 (m, 4 H) 7.69 (dd, J = 8.42, 2.56 Hz, 1 H) 8.64 (d, J = 2.56 Hz , 1 H).

Compound 186: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 2.52 (s, 3 H) 3.94 (s, 3 H) 3.95 (s, 3 H) 6.90 (s, 1 H) 6.92 (d, J = 2.20) Hz, 1 H) 6.98 (dd, J = 8.42, 2.20 Hz, 1 H) 7.27-7.33 (m, 3 H) 7.68 (d, J = 8.42 Hz, 1 H) 7.79 (dd, J = 8.23, 5.31 Hz , 2 H) 8.45 (s, 1 H) 8.61 (s, 1 H).

Compound 187: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.49 (s, 3 H), 3.88 (s, 3 H), 7.10 (d, J = 5.6 Hz, 1 H), 7.26 (d, J =3.5 Hz, 1 H), 7.33-7.38 (m, 2 H), 7.44 (t, J = 8.8 Hz, 2 H), 7.66 (t, J = 8.5 Hz, 1 H), 7.98 (dd, J = 8.7, 5.5 Hz, 2 H), 8.15 (d, J = 5.5 Hz, 1 H), 9.48 (s, 1 H).

Compound 190: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 1.35 (d, J = 6.95 Hz, 6 H) 2.53 (s, 3 H) 3.10 (spt, J = 6.95 Hz, 1 H) 3.93 (s, 3 H) 3.96 (s, 3 H) 6.96 (d, J = 1.83 Hz, 1 H) 7.00 (dd, J = 8.05,1.83 Hz, 1 H) 7.04 (s, 1 H) 7.25 (t, J = 8.60 Hz, 2 H) 7.32 (s, 1 H) 7.35 (s, 1 H) 7.73 (d, J = 8.05 Hz, 1 H) 7.78 (dd, J = 8.60, 5.31 Hz, 2 H).

Compound 191: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 1.34 (d, J = 6.95 Hz, 6 H) 2.58 (s, 3 H) 3.09 (spt, J = 6.95 Hz, 1 H) 3.93 (s, 3 H) 6.93 (s, 1 H) 7.25 (t, J = 8.42 Hz, 2 H) 7.31 (s, 1 H) 7.48 (s, 1 H) 7.63 (d, J = 8.42 Hz, 1 H) 7.70 ( Dd, J = 8.42, 2.56 Hz, 1 H) 7.78 (dd, J = 8.42, 5.85 Hz, 2 H) 8.70 (d, J = 2.56 Hz, 1 H).

Compound 194: ¹ H NMR (360 MHz, CHLOROFORM- d ) δ ppm 2.44 (s, 3 H) 2.60 (s, 3 H) 4.11 (s, 3 H) 6.61 (d, J = 8.05 Hz, 1 H) 6.90 ( t, J = 7.14 Hz, 1 H) 7.32 - 7.43 (m, 4 H) 7.50 - 7.61 (m, 3 H) 7.63 (d, J = 8.05 Hz, 1 H) 8.07 (s, 1 H) 8.23 (d , J = 6.95 Hz, 1 H) 8.49 (d, J = 5.49 Hz, 1 H).

Compound ^{195: 1 H NMR (360 MHz} , DMSO- d 6) δppm 2.47 (s, 3 H), 2.49 (s, 3 H), 3.95 (s, 3 H), 6.79 (s, 1 H), 7.15 ( dd, J = 8.3,2.0 Hz, 1 H), 7.24 (d, J = 2.0 Hz, 1 H), 7.33 (s, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.97 (s , 1 H), 10.02 (s, 1 H).

Pharmacology A) Screening of γ-secretase-modulating activity of the compounds of the invention A1) Method 1

Screening was performed using APP 695-wild-type SKNBE2 cells grown on Dulbecco's Modified Eagle's Medium/Nutrient mixture F-12 (DMEM/NUT-mix F-) supplemented with 1% non-essential amino acid containing 5% serum/Fe 12) (HAM), supplied by Gibco (cat no. 31330-38), cells grown to near confluence.

Screening was performed using the assay described in Citron et al (1997) Nature Medicine 3:67. Briefly, the day before the addition of compound, cells of about ¹⁰⁵ cells / ml were cultured in 96-well flat disk plate, 1% glutamic acid supplemented (Invitrogen, 25030-024) of Ultraculture (Lonza, BE12 In -725F), the compound was added to the cells for 18 hours. The medium was analyzed for Aβ42 and total Aβ by a secondary sandwich ELISA. The toxicity of the compounds was analyzed according to the manufacturer's protocol with WST-1 Cell Proliferation Reagent (Roche, 1 644 807).

To quantify the amount of Aβ42 in the cell supernatant, a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Innotest) was used. β- amyloid _{(1-42), Innogenetics NV, Ghent} , Belgium). The A[beta]42 ELISA was performed essentially according to the manufacturing protocol. Briefly, standard solutions (diluted synthetic Aβ 1-42) were prepared in polypropylene Eppendorf with a final concentration of 8000 to 3.9 pg/ml (1/2 dilution step). Samples, standards, and blank samples (100 microliters) were added to the anti-A[beta]42-coated plates (capture antibodies selectively recognize the C-terminus of the antigen) supplied in the kit. In order to form an antibody-amyloid complex, the culture plate was cultured at 25 ° C for 3 hours. After this incubation and subsequent washing steps, in order to form an antibody-amyloid-antibody-complex, a selective anti-Aβ-antibody conjugate (biotinylated 3D6) was added and cultured for at least 1 hour. After the incubation and appropriate washing steps, Steptavidine-catalase-conjugate was added, and after 30 minutes, 3,3',5,5'-tetramethylbenzidine (TMB)/peroxidation was added. A mixture of hydrogen results in the conversion of the matrix to a colored product. The reaction was stopped with the addition of sulfuric acid (0.9 N), and the color density was measured by an ELISA-reader photometric method with a 450 nm filter.

To quantify the amount of total Aβ in the cell supernatant, samples and standards were added to a 6E10 coated plate. In order to form an antibody-amyloid complex, the culture plates were cultured overnight at 4 °C. After this incubation and subsequent washing steps, in order to form an antibody-amyloid-antibody-complex, a selective anti-Aβ-antibody conjugate (biotinylated 4G8) was added and cultured for at least 1 hour. After the incubation and appropriate washing steps, the avidin-catalase-conjugate was added and after 30 minutes, the Quanta Blu fluorohydrogenase substrate was added according to the manufacturer's instructions (Pierce Corp., Rockford, I1).

To obtain the values described in Table 7a, the S-type dose response curve was analyzed by computerized curve fitting to plot the percent inhibition relative to the concentration of the compound. The 4-parameter equation (mode 205) is used in XL fit to determine the IC ₅₀ . The top and bottom of the curve are fixed at 100 and 0, and the slope of the peak is fixed at 1. The IC ₅₀ represents the concentration of the compound required to inhibit 50% of the biological effect (here, the concentration at which the Aβ peptide concentration is reduced by 50%). The IC ₅₀ values are shown in Table 7a:

To obtain the values described in Table 7b, the data was calculated as the percentage of the maximum amount of amyloid beta 42 measured in the absence of the test compound. The S-type dose response curve was analyzed using nonlinear regression analysis and the percent control relative to the log concentration of the compound was plotted. The IC ₅₀ is determined using the 4-parameter equation, and the values described in Table 7b are the average IC ₅₀ values.

The IC ₅₀ values are shown in Table 7b (nd indicates unmeasured):

A2) Method 2

Screening was performed using APP 695-wild-type SKNBE2 cells grown in supplemented with 1% non-essential amino acid, 2 mM 1-glutamic acid, 15 mM Hepes, 50 U/ml (units/ml) penicillin and 50 μg /ml of streptomycin containing 5% serum/Fe in Dulbecco's Modified Eagle's Medium/Nutrient mixture F-12 (DMEM/NUT-mix F-12) (HAM), supplied by Invitrogen (cat no. 10371-029), cells Grow to near convergence.

Screening was performed using the modifications described in Citron et al (1997) Nature Medicine 3:67. Briefly, in the presence of test compounds at different concentrations tested, supplemented with 1% glutamic acid (Invitrogen, 25030-024), 1% non-essential amino acid (NEAA), 50 U/ml penicillin and 50 μg/ ml of streptomycin Ultraculture (Lonza, BE12-725F), the cells at approximately 10 ⁴ cells / well flat plate were cultured in 384-well plates, cell / compound mixture is 37 ℃, 5% CO ₂ overnight culture. The next day, Aβ42 and total Aβ in the culture medium were analyzed by secondary sandwich immunoassay.

Total Aβ and Aβ42 concentrations in the cell supernatant were quantified using Aphalisa technology (Perkin Elmer). Aphalisa is a sandwich-type assay that uses biotinylated antibodies to attach to avidin coated donor beads and binds antibodies to acceptor beads. In the presence of the antigen, the beads begin to approach and the activation of the donor beads results in the release of a single-line oxygen molecule that is an inducer of the energy transfer string in the acceptor beads, causing the emission of light. To quantify the amount of Aβ42 in the supernatant, a single antibody specific for the C-terminus of Aβ42 (JRF/cAβ42/26) was coupled to the acceptor beads and used for N-terminal specificity of Aβ(JRF/AβN/25). The biotinylated antibody reacts with the donor beads. In order to quantify the amount of total Aβ in the supernatant, a monoclonal antibody specific for the N-terminus of Aβ (JRF/AβN/25) was coupled to the acceptor bead, and an organism specific for the central region of Aβ (biotinylated 4G8) was used. The primed antibody reacts with the donor beads.

To obtain the values described in Table 7c, the data was calculated as a percentage of the maximum amount of amyloid beta 42 measured in the absence of the test compound. The S-type dose response curve was analyzed using nonlinear regression analysis and the percent control relative to the log concentration of the compound was plotted. The IC ₅₀ is determined using a 4-parameter equation.

The values described in Table 7c are IC ₅₀ values.

B) Confirmation of in vivo efficacy

The A?42 lowering agent of the present invention can treat AD in a mammal such as a human, or demonstrate efficacy in an animal model, such as, but not limited to, mouse, rat or guinea pig. Mammals may not be diagnosed with AD, or may not have the genetic predisposition to AD, but may be transgenic so as to overproduce and eventually deposit A[beta] in a similar manner as seen in humans suffering from AD.

The Aβ42 lowering agent can be administered in any standard manner using any standard method, for example, the Aβ42 lowering agent can be in the form of an oral liquid, lozenge or capsule, or via injection, but not limited thereto. The A[beta]42 lowering agent can be administered in any dose sufficient to significantly reduce the concentration of blood, plasma, serum, cerebrospinal fluid (CSF) or A[beta]42 in the brain.

To determine whether acute administration of A[beta]42 lowering agents can reduce A[beta]42 concentrations in vivo, non-genetically transgenic rodents, such as mice or rats, are used. Alternatively, a Tg2576 mouse of two to three months old with APP695 containing "Swedish" variation, or a gene-transforming mouse model developed by Dr. Fred Van Leuven (KULeuven, Belgium) can be used, which has human Neuronal specific expression of clinical mutations in amyloid precursor protein [V717I] (Moechars et al., 1999 J. Biol. Chem. 274, 6843). Young gene-transferred mice have high concentrations of A[beta] in the brain but no detectable A[beta] deposition. At about 6-8 months of age, the genetically-transferred mice began to show spontaneous and progressive accumulation of β-amyloid (Aβ) in the brain, eventually producing amyloid plaques in the hippocampus, hippocampus and cortex. Animals treated with A[beta]42 lowering agents were tested and compared to untreated or vehicle treated, and brain concentrations of soluble A[beta]42 and total A[beta] were quantified using standard techniques, for example using ELISA. Once the time course of the onset of the effect can be established, the treatment period varies from hour to day and is adjusted according to the result of Aβ42 reduction.

A general procedure for measuring Aβ42 decline in vivo has been shown, but it is only one of many that can be used to optimize changes in detectable A[beta] concentrations, such as A[beta]42 lowering compounds formulated to contain 20% Captisol Water (β-cyclodextrin sulfobutyl ether) or 20% hydroxypropyl β cyclodextrin. The A[beta]42 lowering agent is administered to the fasted overnight animals in a single oral dose or in any acceptable route of administration. Four hours later, the animals were sacrificed and analyzed for A[beta]42 concentration.

The head was excised and bled, and blood was collected in an EDTA-treated collection tube. The blood was centrifuged at 1900 g for 10 minutes at 4 ° C, and plasma was recovered and rapidly frozen for subsequent analysis. The brain is removed from the cranial and hindbrain, the cerebellum is removed and the left and right hemispheres are separated. The left brain was stored at -18 ° C for quantitative analysis of test compound concentrations. The right brain was rinsed with phosphate buffered saline (PBS) buffer and immediately frozen on dry ice and stored at -80 °C until homogenized for biochemical analysis.

The mouse brain was resuspended per gram of tissue in 10 volumes of 0.4% DEA (diethylamine) / 50 mM NaCl pH 10 containing protease inhibitor (Roche-11873580001 or 04693159001) (for non-gene transfer) Animal) or 0.1% 3-[(3-cholestyramine)-dimethyl-ammonium]-1-propane sulfonate (CHAPS) in tris buffered saline (TBS) (for gene transfer animals) For example, 0.158 g of brain, adding 1.58 ml of 0.4% DEA. The oxygen sample was vortexed on ice for 20 seconds at 20% power (pulse mode). The homogenate was centrifuged at 221.300 x g for 50 minutes. The resulting high speed supernatant was then transferred to a new tube and arbitrarily further purified prior to the next step. A portion of the supernatant was neutralized with 10% 0.5 M Tris-HCl and used to quantify total Aβ.

The supernatant obtained was purified on a Water Oasis HLB reverse phase column (Waters Corp., Milford, MA) and the non-specific immunoreactive material was removed from the brain lysate prior to subsequent A[beta] detection. Using a vacuum manifold, all of the solution was passed through the column at a rate of about 1 ml per minute, thus adjusting the vacuum pressure throughout the procedure. Prior to the 1 ml H ₂ O balance to the column of 1 ml 100% MeOH pretreatment. The unneutralized brain lysate was filled on the column, and the sample was then washed twice with a first wash of 1 ml of 5% MeOH and a second wash of 1 ml of 30% MeOH. Finally, with 2% NH ₄ OH 90% MeOH solution of the extract Aβ from the wash column to the 100 x 30 mm glass test tube. The eluate was then transferred to a 1.5 ml tube and concentrated on a high speed vacuum concentrator at 70 ° C for about 1.5-2 hours. The concentrated A[beta] was then resuspended in an UltraCULTURE universal serum free medium (Cambrex Corp., Walkersville, MD) with additional protease inhibitor according to the manufacturer's instructions.

To quantify the amount of Aβ42 in the soluble fraction of the brain homogenate, a commercially available enzyme-linked immunosorbent assay (ELISA) kit (eg Innotest) is used. β-Amyloid (1-42), Innogenetics NV, Ghent, Belgium). The Aβ42 ELISA was performed using a culture tray that was only used for the kit. Briefly, standard solutions (diluted Aβ 1-42 dilutions) were prepared in Ultraculture's 1.5 ml Eppendorf tube at a final concentration ranging from 25,000 to 1.5 pg/ml. Samples, standards, and blank samples (60 microliters) were added to the anti-A[beta]42-coated plates (capture antibodies selectively recognize the C-terminus of the antigen). In order to form an antibody-amyloid complex, the plates were incubated overnight at 4 °C. After this incubation and subsequent washing steps, to form an antibody-amyloid-antibody-complex, a selective anti-Aβ-antibody conjugate (biotinylated detection antibody, such as biotinylated 4G8 (Covance Research Products, Dedham) is added. , MA)), and culture for at least 1 hour. After the incubation and appropriate washing steps, the avidin-catalase-conjugate was added and after 50 minutes, the Quanta Blu fluorescent catalase substrate (Pierce Corp., Rockford, I1) was added according to the manufacturer's instructions. A kinetic read (excitation 320/radiation 420) was performed every 5 minutes for 5 minutes. To quantify the total amount of A[beta] of the soluble fraction in the brain homogenate, samples and standards were added to the JRF/rA[beta]/2-coated plates. In order to form an antibody-amyloid complex, the plates were incubated overnight at 4 °C. The ELISA is then performed as described for A[beta]42.

In this mode, it is advantageous to reduce at least 20% A?42 compared to the animal being treated.

The results are shown in Table 8:

C) Effect on Notch-treatment activity of γ-secretase-complex Analysis without Notch cells The Notch transmembrane domain was cleaved with Gamma secretase to release the C-terminal domain (NICD) in Notch cells. Notch is a signaling protein that plays an important role in the development process, and therefore, the compound preferably does not exhibit an effect on the Notch-treatment activity of the γ-secretase-complex. To monitor the effect of compounds on NICD production, a recombinant Notch matrix (N99) was prepared. Notch fragment comprising (V1711-E1809) mouse, N terminal methionine and C-terminal FLAG sequence (DYDDDDK) is represented in a matrix of Notch E. coli, and purified on M2 affinity column containing an anti-matrix of the -FLAG . Typically, no Notch cell assay consisted of a 0.3-0.5 μM Notch matrix, a concentrated preparation of horse-secretase, and 1 μM of test compound (compounds 16, 18 and 106 of the invention). The control group consisted Gamma secretase inhibitor (GSI), for example (2S) - N - [2- (3,5- difluorophenyl) acetyl yl] -L- propylamine acyl-2-phenyl - Gly 1,1-dimethylethylamine (DAPT) or (2S)-2-hydroxy-3-methyl- N -[(1S)-1-methyl-2-keto-2-[[ (1S)-2,3,4,5-tetrahydro-3-methyl-2-keto-1H-3-phenazin-1-yl]amino]ethyl]-butanamine (Smasi Semagacestat, with DMSO, a final concentration of DMSO of 1%. The recombinant Notch matrix was pretreated with 17 μM DTT (1,4-dithiothreitol) and 0.02% SDS (sodium lauryl sulfate) and heated at 65 °C for 10 minutes. A mixture of matrix, plus horse secretase and compound/DMSO was incubated at 37 ° C for 6 to 22 hours. The 6 hour incubation was sufficient to produce the maximum amount of NICD and the lysate was allowed to settle for another 16 hours. The reaction product was subjected to SDS PAGE (sodium lauryl sulfate polyacrylamide colloidal gel electrophoresis) and Western blotting method. The ink spot was anti-Flag M2 antibody, and then labeled with LI-COR infrared secondary antibody as a probe, and Odyssey was used. Infrared Imaging System (LI-COR Biosciences) analysis. In the cell-free Notch assay, no test compound (compounds 16, 18 and 106 of the invention) was inhibited by the addition of horse secretase to inhibit C99 cleavage, whereas the production of NICD was controlled by GSI (DAPT or Semagacestat). Blocked. Therefore, it was confirmed that the compounds 16, 18 and 106 of the present invention did not show the effect of the Notch-treatment activity (production of NICD) of the γ-secretase-complex. Analysis based on Notch cells

Analysis based on Notch cells was based on the interaction of Notch and its ligands in the co-culture system and monitoring of NICD production using the Dual-Glo Luciferase Assay System (Promega). N2-CHO and DL-CHO two stable cell lines were established to express full length mouse Notch2 and Delta. Cells expressing mouse Notch were also transfected into pTP1-Luc and pCMV-Rluc two plastids to express firefly and jellyfish ( Renilla ) luciferase. The TP1 promoter controls the performance of firefly luminescent enzymes, which reflect NICD activity. The CMV promoter driving the jellyfish luminescent enzyme does not reflect the NICD activity and is therefore used to control transfection efficiency and compound toxicity.

The day before transfection N2-CHO cells at 1x10 ⁵ / holes connected to the weight 24-well plates. On the second day, cells were double-transfected with 3 μg/well pTP1-Luc (expressing firefly luciferase) and 0.3 ng/well pCMV-RLuc (expressing jellyfish luciferase). After 6 hours of incubation, washing N2-CHO cells were transfected by, and adding DL-CHO cells (2 x 10 ⁵ cells / well).

The compound was premixed with the DL-CHO cell suspension in a five-point curve. In general, compound treatment was repeated with a 1:10 dilution (3 μM-0.3 nM) in DMSO. The final concentration of DMSO in a given medium was 1%. The control group containing the transfected cells and the transfected cells were only treated with GSI or DMSO, and subjected to cold light enzyme analysis after 16 hours of co-culture and compound treatment.

The cold light enzyme assay was performed according to the manufacturer's instructions. Briefly, the cells were washed with PBS (phosphate buffered saline), dissolved in Passive Lysis Buffer (Promega), and incubated at room temperature for 20 minutes. The lysate was mixed with Dual-Glo Luciferase Reagent and the luminescence signal was measured on an EnVision 2101 Multilabel reader to measure the luminescence activity of the firefly. Dual-Glo Stop & Glo Reagent was then added to each well and the jellyfish luminescent enzyme signal was measured.

The results based on analysis of Notch cells were consistent with those of cell-free NICD analysts. Analysis based on readings of the luminescence, and based on Notch DAPT average IC ₅₀ values Division Maxi Te analysis of each cell 45 nM and 40 nM, and vice versa, a compound of this invention 18 is non-inhibitory.

C. Composition Examples

Examples of the use of these "active ingredient" embodiment (ai) based on the formula (I), including any stereochemically isomeric forms, its N - oxide, their pharmaceutically acceptable salt or solvate thereof; in particular Regarding any of the exemplified compounds.

A general embodiment of the side of the formulation used in the present invention is as follows:

Lozenge

Active ingredient 5 to 50 mg

Dicalcium phosphate 20 mg

Lactose 30 mg

Talc 10 mg

Magnesium stearate 5 mg

Potato starch added to 200 mg

2. Suspension

An aqueous suspension for oral administration is prepared, thus containing 1 to 5 mg of active ingredient per ml, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol, and 1 ml of water with water.

3. Injection

The parenteral composition was prepared by stirring 1.5% (w/v) active ingredient in 0.9% NaCl solution or in water containing 10% by volume of propylene glycol.

Ointment

Active ingredient 5 to 1000 mg

Stearyl alcohol 3 g

Lanolin 5g

White petroleum 15 grams

Water added to 100 grams

In this embodiment, the active ingredient may be replaced by an equivalent amount of any of the compounds of the invention, especially in an equivalent amount of any exemplified compound.

A reasonable change is not to be seen as a departure from the scope of the invention, and it is obvious that the invention as described herein is varied in many ways by those skilled in the art.

Claims (17)

a compound of formula (I) or a stereoisomeric form thereof, Wherein Het ¹ is a 5- or 6-membered aromatic heterocyclic ring having the formula (a-1), (a-2), (a-3), (a-4) or (a-5): R ⁰ is H or C _1-4 alkyl; R ¹ is H, C _1-4 alkyl or C _1-4 alkoxy C _1-4 alkyl; R ² is C _1-4 alkyl; X is O, or S; G ¹ is CH or N; G ² is CH, N or substituted by C _1-4 alkyl of C; provided that G ¹ and G ² are not simultaneously N; G ³ is CH or N; R ^10a And R ^{10b are} each independently hydrogen or C _1-4 alkyl; A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ² , A ³ and A ^{4 are} each independently CH, CF or N; only A ¹ , A ² , A ³ and A ^{4 are at} most N; Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-1) or (b-2): Z ¹ is CH or N; Z ² is CR ^4a or N; Z ³ is CH or N; only Z ¹ , Z ² and Z ^{3 are at} most one N; Y ¹ is CH or N; Y ² is CR ^4b or N; Y ³ is CH or N; wherein at most one of Y ¹ , Y ² and Y ³ is N; R ^4a is H; halogen; C _1-4 alkoxy; cyano; ring C _3-7 alkyl; a C _1-4 alkylcarbonyl group; a C _1-4 alkoxycarbonyl group; or a C _1-4 alkyl group, which is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and an amine group; R ^4b is H; halogen; C _1-4 alkoxy; cyano; cyclo C _3-7 alkyl; or C _1-4 alkyl, optionally optionally selected from halo and amine groups via one or more Substituted by a group of substituents; R ⁵ is H; halogen; cyano; C _1-4 alkoxy; C _2-6 alkenyl; or C _1-6 alkyl, optionally via one or more Substituted independently by a substituent selected from the group consisting of C _1-4 alkoxy and halogen; R ^6a is C _2-6 alkyl substituted with one or more halogen substituents; C _1-6 alkyl, Optionally consisting of one or more of each independently selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropyranyl, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkyl Substituent substituents; ring C _3-7 alkyl; C _{1- 4} -alkylcarbonyl; tetrahydropyranyl; Ar; R ⁸ R ⁹ N-carbonyl; or CH ₂ -O-Ar; R ^6b is C _2-6 alkyl substituted with one or more halogen substituents; _{a 1-6} alkyl group optionally arbitrarily selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropyranyl, cyclo C _3-7 alkoxy, and ring C _{3 -7} group consisting of alkyl substituents; C _3-7 cycloalkyl group; a phenyl group substituted with one or more substituents of the group C _3-7 cycloalkyl group, the phenyl group optionally substituted with one or more Substituted by a halogen substituent; piperidinyl; morpholinyl; pyrrolidinyl; NR ⁸ R ⁹ ; tetrahydropyranyl; O-Ar; C _1-6 alkoxy; C _1-6 alkylthio; ; CH ₂ —O—Ar; S—Ar; NCH ₃ —Ar; or NH—Ar; wherein each piperidinyl, morpholinyl, and pyrrolidinyl group may be optionally independently selected from C ₁ through one or more Substituted with a substituent group consisting of _-4 alkyl, C _2-6 alkenyl, C _1-4 alkylcarbonyl, halogen, and C _1-4 alkoxycarbonyl; wherein each Ar is independently phenyl, Optionally substituted by one or more of each independently selected from the group consisting of halogen, C _1-4 alkoxy, cyano, NR ⁸ R ⁹ , morpholinyl, C _1-4 alkyl, and substituted with one or more halogen substituents C _a substituent substituted with a group consisting of _1-4 alkyl groups; a pyridyl group optionally exemplified by one or more of each independently selected from the group consisting of halogen, C _1-4 alkoxy, cyano, C _1-4 alkyl, and Substituted by a substituent group consisting of one or more halogen substituent-substituted C _1-4 alkyl groups; An azolyl group optionally substituted with one or more C _1-4 alkyl substituents; or a thienyl group optionally substituted with one or more halogen substituents; each R ^{8 is} independently H or C _1-4 An alkyl group; each R ^{9 is} independently H or C _1-4 alkyl; R ⁷ is H, C _1-6 alkyl optionally substituted one or more of each independently selected from the group consisting of halogen, phenyl, and C ₁ Substituted by a substituent group consisting of _-4 alkoxy groups; or a pharmaceutically acceptable addition salt thereof. A compound according to claim 1 or a stereoisomeric form thereof, wherein Het ¹ is a 5-membered aromatic heterocyclic ring having the formula (a-1), (a-2), (a-3) or (a- 4) R ⁰ is H or C _1-4 alkyl; R ¹ is H or C _1-4 alkyl; R ² is C _1-4 alkyl; X is O or S; G ¹ is CH or N; ² is CH, N or C substituted by C _1-4 alkyl; only G ¹ and G ^{2 are} not N at the same time; G ³ is CH or N; A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ^2, A ³ and A ⁴ each independently CH, CF or N; provided that A ^1, A ^2, A ³ and A ⁴ both up to N; Het ² is a bicyclic 9 An aromatic heterocyclic ring having the formula (b-1) or (b-2): Z ¹ is CH or N; Z ² is CR ^4a ; Z ³ is CH; Y ¹ is CH or N; Y ² is CR ^4b ; Y ³ is CH; R ^4a is H; halogen; C _1-4 alkoxy a cyano group; or a C _1-4 alkyl group optionally substituted by one or more halogen substituents; R ^4b is H; halogen; C _1-4 alkoxy; cyano; or optionally one or more a halogen substituent-substituted C _1-4 alkyl group; R ⁵ is H; halogen; cyano; or C _1-6 alkyl, optionally exemplified by one or more of each independently selected from C _1-4 alkoxy and Substituted by a substituent of the group consisting of halogen; R ^6a is a C _2-6 alkyl group substituted by one or more halogen substituents; C _1-6 alkyl group optionally optionally selected from piperidine by one or more a substituent substituted by a group consisting of Ar, C, _1-6 alkoxy, tetrahydropentanyl, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkyl; cyclo C _3-7 alkane a tetrahydropyranyl group; Ar; or CH ₂ -O-Ar; R ^6b is a C _2-6 alkyl group substituted by one or more halogen substituents; a C _1-6 alkyl group, optionally passed through a Or a plurality of each independently selected from the group consisting of piperidinyl, Ar, C _1-6 alkoxy, tetrahydropyranyl, cyclo C _3-7 alkoxy, and cyclo C _3-7 alkyl Substituent substitution _3-7 alkyl; piperidinyl; morpholinyl; pyrrolidinyl; NR ⁸ R ⁹ ; tetrahydropyranyl; O-Ar; C _1-6 alkoxy; C _1-6 alkylthio; Ar; CH ₂ -O-Ar; S-Ar; NCH ₃ -Ar or NH-Ar; wherein each piperidinyl, morpholinyl, and pyrrolidinyl group may be optionally independently selected from C ₁ by one or more _-4 alkyl, C _2-6 alkenyl, C _1-4 alkylcarbonyl, halo, and C _1-4 alkoxy carbonyl group consisting of substituents; wherein each Ar is independently phenyl, which Optionally substituted by one or more of each independently selected from halo, C _1-4 alkoxy, cyano, NR ⁸ R ⁹ , morpholinyl, C _1-4 alkyl, and substituted by one or more halogen substituents Substituting a substituent of the group consisting of C _1-4 alkyl groups; or pyridyl group optionally arbitrarily selected from halogen, C _1-4 alkoxy, cyano, C _1-4 alk. And a substituent substituted by a group consisting of C _1-4 alkyl substituted by one or more halogen substituents; each R ^{8 is} independently H or C _1-4 alkyl; each R ^{9 is} independently H Or C _1-4 alkyl; R ⁷ is H, optionally substituted by one or more groups independently selected from the group consisting of halogen, phenyl, and C _1-4 alkoxy a C _1-6 alkyl group substituted by a group; or a pharmaceutically acceptable addition salt thereof. The compound of claim 1 or a stereoisomeric form thereof, wherein A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ² , A ³ and A ⁴ each Independently CH, CF or N; only A ¹ , A ² , A ³ and A ^{4 are at} most N; Z ² is CR ^4a ; R ^4a is H; halogen; cyano; ring C _3-7 alkyl; a C _1-4 alkylcarbonyl group; a C _1-4 alkoxycarbonyl group; or a C _1-4 alkyl group, which is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and an amine group; R ⁵ is H; halogen; C _1-4 alkoxy; C _2-6 alkenyl; or C _1-6 alkyl, optionally substituted by one or more C _1-4 alkoxy substituents; ^6a is a C _1-6 alkyl group optionally substituted by one or more substituents each independently selected from the group consisting of Ar, C _1-6 alkoxy and tetrahydropyranyl; ring C _3-7 Alkyl; C _1-4 alkylcarbonyl; tetrahydropyranyl; Ar; R ⁸ R ⁹ N-carbonyl; R ^6b is C _2-6 alkyl substituted with one or more halogen substituents; C _{1- a 6} alkyl group optionally substituted by one or more substituents each independently selected from the group consisting of Ar, C _1-6 alkoxy, tetrahydropentanyl and cyclo C _3-7 alkyl; _3-7 alkyl; One or more phenyl substituent-substituted ring C _3-7 alkyl groups optionally substituted with one or more halogen substituents; unsubstituted piperidinyl; NR ⁸ R ⁹ ; tetrahydropyranyl Ar; or CH ₂ -O-Ar; wherein each Ar is independently a phenyl group, optionally exemplified by one or more of each independently selected from the group consisting of halogen, C _1-4 alkoxy, C _1-4 alkyl, and Substituted by a substituent group consisting of one or more halogen substituent-substituted C _1-4 alkyl groups; An azolyl group optionally substituted with one or more C _1-4 alkyl substituents; or a thienyl group optionally substituted with one or more halogen substituents; each R ^{8 is} independently H or C _1-4 Alkyl; each R ^{9 is} independently H or C _1-4 alkyl; R ⁷ is C _1-6 alkyl optionally substituted with one or more C _1-4 alkoxy substituents; or a pharmaceutical thereof Acceptable addition salts are acceptable. A compound according to claim 1 or a stereoisomeric form thereof, wherein Het ¹ is a 5-membered aromatic heterocyclic ring having the formula (a-1), (a-2), (a-3) or (a- 4); R ⁰ is H or C _1-4 alkyl; R ¹ is H or C _1-4 alkyl; R ² is C _1-4 alkyl; X is O or S; G ¹ is CH; G ² Is CH or C _1-4 alkyl substituted C; G ³ is CH; A ¹ is CR ³ or N; wherein R ³ is H, halogen or C _1-4 alkoxy; A ² is CH or N; A ³ and A ⁴ is CH; Het ² is 9-membered bicyclic aromatic heterocyclic ring, having the formula (b-1) or (b-2); where Z ¹ is CH or N; Z ² is CR ^4a; Z ³ is CH; Y ¹ is CH or N; Y ² is CR ^4b ; Y ³ is CH; R ^4a is H or halogen; R ^4b is H, halogen or C _1-4 optionally substituted by one or more halogen substituents Alkyl; R ⁵ is H, or C _1-4 alkyl; R ^6a is Ar; or C _1-6 alkyl optionally substituted with one Ar; R ^6b is Ar; substituted with one or more halogen substituents a C _2-6 alkyl group; a C _1-6 alkyl group optionally substituted with one or more Ar substituents; or CH ₂ —O-Ar; wherein each Ar is independently a phenyl group, optionally passed through one or each independently selected from the group consisting of a plurality of halogen, C _1-4 alkoxy, C _1-4 alkyl, and substituted with one or more halogen substituents taken Consisting of C _1-4 alkyl group substituted with the substituent group; R ⁷ is optionally substituted with one or more C _1-4 alkoxy substituents of the substituted C _1-6 alkyl group; or a pharmaceutically acceptable Addition salt. A compound according to claim 1 or a stereoisomeric form thereof, wherein Het ¹ is a 5- or 6-membered aromatic heterocyclic ring having the formula (a-1) or (a-5); and R ⁰ is H or C. _1-4 alkyl; R ¹ is H or C _1-4 alkyl; X is O; R ^10a and R ^{10b are} each independently hydrogen or C _1-4 alkyl; A ¹ is CR ³ or N; wherein R ³ Is a C _1-4 alkoxy group; A ² , A ³ and A ⁴ are CH; Het ² is a 9-membered bicyclic aromatic heterocyclic ring having the formula (b-1) or (b-2); Z ¹ and Z ³ Is CH; Z ² is CR ^4a ; R ^4a is H or halogen; Y ¹ and Y ³ are CH; Y ² is CR ^4b ; R ^4b is H or C _1-4 alkoxy; R ⁵ is H or methyl R ^6a is C _1-6 alkyl; R ^6b is phenyl optionally substituted with one or more halogen substituents; R ⁷ is C _1-6 alkyl; or a pharmaceutically acceptable addition salt thereof. A compound according to claim 5 or a stereoisomeric form thereof, wherein Het ¹ has the formula (a-1). A compound according to claim 5 or a stereoisomeric form thereof, wherein Het ² has the formula (b-2). A compound according to claim 5 or a stereoisomeric form thereof, wherein R ^4a is halogen. A compound according to claim 8 or a stereoisomeric form thereof, wherein R ^4a is fluorine. A compound according to claim 5 or a stereoisomeric form thereof, wherein R ^4b is H or methoxy. A compound according to claim 1 or a stereoisomeric form thereof, wherein the compound is selected from the group consisting of 2-(4-fluorophenyl)-1-(1-methylethyl) -N -[6-(2-methyl-5- Azyl)-3-pyridyl]-1 H -benzimidazol-4-amine, 6-fluoro- N- [3-methoxy-4-(4-methyl-5- Azyl)phenyl]-2-(2-methylpropyl)-imidazole [1,2- a ]pyridine-8-amine HCl, 2-(4-fluorophenyl)-6-methoxy- N -[3-methoxy-4-(2-methyl-5- Thiazolyl) phenyl] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (4-methyl - 5- Thiazolyl) phenyl] -1-methyl -1 H - benzimidazol-4-amine, 2- (4-fluorophenyl) - N - [3- methoxy-4- (2-methyl - 4-pyridyl)phenyl]-1-(1-methylethyl)-1 H -benzimidazole-4-amine, including any stereochemically isomeric form thereof, or a pharmaceutically acceptable addition salt thereof Or solvate. The scope of the patent compound or a stereoisomeric forms, Paragraph 1, wherein the compound is 2- (4-fluorophenyl) -1- (1-methylethyl) - N - [6- (2- methyl -5- Azyl)-3-pyridyl]-1 H -benzimidazole-4-amine. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1 to 12, or Stereoisomeric pattern. The compound of any one of claims 1 to 12, or a stereoisomeric form thereof, for use as a medicament. The compound of any one of claims 1 to 12, or a stereoisomeric form thereof, for use in the treatment or prevention of a disease selected from the group consisting of Alzheimer's disease, traumatic brain injury, mild cognitive impairment, aging, dementia, Luis's dementia, cerebral amyloid angiopathy, multiple infarct dementia, Down's syndrome, Parkinson's disease-related dementia, and β-amyloid-related dementia. A compound according to claim 15 or a stereoisomeric form thereof, wherein the disease is Alzheimer's disease. A use of a compound according to any one of claims 1 to 12, or a stereoisomeric form thereof, for the manufacture of a medicament for regulating the activity of a gama-secretase.